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Chen X, Bao W, Liu K, Jing N, Du G, Jiang L, You Q, Zhang Y, Xu P, Cheng C, Wang N, Xi X, Wang M, Liu Y, Wang J, Zhao H, Zhang S, Wu D, Ng CF, Pan J, Xue W, Gao WQ, Zhang P, Zhang K, Zhu HH. O-GalNAc Glycosylation Activates MBL-Mediated Complement and Coagulation Cascades to Drive Organotropic Metastasis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e04809. [PMID: 40492591 DOI: 10.1002/advs.202504809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 05/22/2025] [Indexed: 06/12/2025]
Abstract
Liver metastasis is prevalent among patients with neuroendocrine prostate cancer (NEPC) and other types of neuroendocrine (NE) cancers, featuring with an aggressive clinical course and a dismal prognosis. However, the cellular and molecular mechanisms underlying liver-specific metastatic tropism in NE cancers remain poorly understood. Intriguingly, it is found that NEPC liver metastatic foci are frequently associated with thrombi. NEPC cells express an aberrantly elevated level of glycosyltransferase Galnt9. Notably, the Galnt9-mediated O-GalNAc glycosylation on the cell membrane of NE cancer cells, particularly on the adhesion molecule Annexin A2, activates the mannose-binding lectin (MBL) complement signaling in the liver. This cascade stimulates platelet activation and thrombus formation, ultimately facilitating hepatic metastasis of NEPC. Inhibition of O-GalNAc glycosylation or knockdown of Galnt9 demonstrates efficacy in restraining the liver metastasis of NEPC, small cell lung cancer (SCLC), and colorectal neuroendocrine cancer. These findings identify Galnt9-mediated O-GalNAc glycosylation as a targetable mechanism driving liver metastasis through activation of MBL complement and coagulation cascades across a broad spectrum of NE cancers.
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Affiliation(s)
- Xinyu Chen
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Wei Bao
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Kaiyuan Liu
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Na Jing
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Genyu Du
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Luyao Jiang
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Qian You
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Yingchao Zhang
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Penghui Xu
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
- Med-X research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Chaping Cheng
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Nan Wang
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Xialian Xi
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Mingyue Wang
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Yiyun Liu
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Jinming Wang
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Huifang Zhao
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Shilei Zhang
- Department of Pathology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Dinglan Wu
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, 999077, China
| | - Chi-Fai Ng
- S.H. Ho Urology Centre, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, 999077, China
| | - Jiahua Pan
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Wei Xue
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Wei-Qiang Gao
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
- Med-X research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Pengcheng Zhang
- School of Biomedical Engineering, Shanghai Tech University, Shanghai, 201210, China
| | - Kai Zhang
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Helen He Zhu
- State Key Laboratory of Systems Medicine for Cancer, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
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2
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Yuan Z, Tao D, Yang D, Jiang Y, Munai E, Zeng S, Zhou Z, Zhou W, Wu Y. Prophylactic cranial irradiation in resected early stage small cell lung cancer: an updated systematic review and meta-analysis. Radiat Oncol 2025; 20:82. [PMID: 40394671 PMCID: PMC12093860 DOI: 10.1186/s13014-025-02644-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 04/22/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND The use of prophylactic cranial irradiation (PCI) in early stage small cell lung cancer (SCLC) patients post-surgery remains controversial. This meta-analysis aimed to evaluate the efficacy of PCI in resected early stage SCLC patients. METHODS Relevant literature was reviewed through PubMed, Cochrane, and Embase databases. The pooled hazard ratios (HRs) for overall survival (OS) were analyzed for the overall population, as well as for pathologically node-negative (pN0) and pathologically node-positive (pN+) patients. We also assessed the pooled HRs for brain metastasis-free survival (BMFS) in all patients. Sensitivity analyses were conducted to validate these results. RESULTS A total of 13 retrospective studies were included, encompassing 3,530 postoperative SCLC patients, of whom 880 received PCI treatment. In the overall patient population, PCI significantly improved OS compared to non-PCI group (HR: 0.66, 95% CI 0.58-0.74, p < 0.001). For pN0 patients, there was no significant OS benefit from PCI (HR: 0.85, 95% CI 0.65-1.10, p = 0.22). In contrast, pN + patients showed a significant OS improvement with PCI (HR: 0.52, 95% CI 0.41-0.66, p < 0.001). Furthermore, PCI significantly improved BMFS in all patients (HR: 0.42, 95% CI 0.29-0.60, p < 0.001). Sensitivity analyses confirmed the stability of these results. CONCLUSIONS PCI was associated with a significant improvement in OS and BMFS in resected early stage SCLC patients. The benefits of PCI were particularly pronounced in pN + patients, whereas pN0 patients did not experience a significant OS benefit. These findings supported the selective use of PCI based on nodal status to optimize treatment outcomes in postoperative SCLC patients.
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Affiliation(s)
- Ze Yuan
- Department of Radiation Oncology, Chongqing University Cancer Hospital, 181, Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Dan Tao
- Department of Radiation Oncology, Chongqing University Cancer Hospital, 181, Hanyu Road, Shapingba District, Chongqing, 400030, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Dingyi Yang
- Department of Radiation Oncology, Chongqing University Cancer Hospital, 181, Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Yong Jiang
- Department of Radiation Oncology, Chongqing University Cancer Hospital, 181, Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Erha Munai
- Medical School of Chongqing University, Chongqing University, Chongqing, China
| | - Siwei Zeng
- Medical School of Chongqing University, Chongqing University, Chongqing, China
| | - Zhiying Zhou
- Medical School of Chongqing University, Chongqing University, Chongqing, China
| | - Wei Zhou
- Department of Radiation Oncology, Chongqing University Cancer Hospital, 181, Hanyu Road, Shapingba District, Chongqing, 400030, China.
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yongzhong Wu
- Department of Radiation Oncology, Chongqing University Cancer Hospital, 181, Hanyu Road, Shapingba District, Chongqing, 400030, China.
- Medical School of Chongqing University, Chongqing University, Chongqing, China.
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Nalkiran I, Sevim Nalkiran H, Ozcelik N, Kivrak M. In Silico Identification of LSD1 Inhibition-Responsive Targets in Small Cell Lung Cancer. Bioengineering (Basel) 2025; 12:504. [PMID: 40428124 PMCID: PMC12108737 DOI: 10.3390/bioengineering12050504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2025] [Revised: 04/28/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid progression, high metastatic potential, and limited therapeutic options. Lysine-specific demethylase 1 (LSD1) has been identified as a promising epigenetic target in SCLC. RG6016 (ORY-1001) is a selective LSD1 inhibitor currently under clinical investigation for its antitumor activity. In this study, publicly available RNA-Seq datasets from SCLC patient-derived xenograft (PDX) models treated with RG6016 were reanalyzed using bioinformatic approaches. Differential gene expression analysis was conducted to identify genes responsive to LSD1 inhibition. Candidate genes showing significant downregulation were further evaluated by molecular docking to assess their potential interaction with RG6016. The analysis identified a set of differentially expressed genes following RG6016 treatment, including notable downregulation of MYC, UCHL1, and TSPAN8. In silico molecular docking revealed favorable docking poses between RG6016 and the proteins encoded by these genes, suggesting potential direct or indirect targeting. These findings support a broader mechanism of action for RG6016 beyond its known interaction with LSD1. This study demonstrates that RG6016 may exert its antitumor effects through the modulation of additional molecular targets such as MYC, UCHL1, and TSPAN8 in SCLC. The combined bioinformatic and molecular docking analyses provide new insights into the potential multi-target profile of RG6016 and indicate the need for further experimental validation.
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Affiliation(s)
- Ihsan Nalkiran
- Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, 53020 Rize, Türkiye; (I.N.); (H.S.N.)
| | - Hatice Sevim Nalkiran
- Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, 53020 Rize, Türkiye; (I.N.); (H.S.N.)
| | - Neslihan Ozcelik
- Department of Chest Diseases, Faculty of Medicine, Recep Tayyip Erdogan University, 53020 Rize, Türkiye;
| | - Mehmet Kivrak
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Recep Tayyip Erdogan University, 53020 Rize, Türkiye
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Li M, Gu X, Yang J, Zhang C, Zhou Y, Huang P, Wang X, Zhang L, Jiang L, Zhai L, Yu M, Cheng G, Yang L. Luteolin: A potential therapeutic agent for respiratory diseases. Eur J Pharmacol 2025; 999:177699. [PMID: 40324574 DOI: 10.1016/j.ejphar.2025.177699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 04/10/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025]
Abstract
Acute lung injury, COVID-19, lung cancer, and asthma are a few of the respiratory conditions that are the main causes of morbidity and mortality worldwide. The increasing incidence and mortality rates have attracted significant attention to the prevention and treatment of these conditions. In recent years, there has been a renewed interest in utilizing naturally derived compounds as therapeutic agents for respiratory diseases. Luteolin (Lut), a flavonoid compound, possesses an extensive range of pharmacological characteristics, encompassing anti-inflammatory, antioxidative, antineoplastic, and antimicrobial activities. However, a comprehensive summary of Lut's therapeutic effects and mechanisms in respiratory diseases remains lacking. This review examines the physicochemical properties, toxicity, and avenues of Lut's action in respiratory ailments. Lut exerts therapeutic effects through pathways such as nuclear factor kappa-B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), mitogen-activated protein kinase (MAPK), janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), and pyroptosis, modulating key processes such as the suppression of inflammatory mediators, attenuation of oxidative assault, and induction of apoptosis in lung cancer cells. This review strives to provide critical realizations into respiratory disease therapeutics and contribute to the foundation for drug development.
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Affiliation(s)
- Meng Li
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xinru Gu
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Jiaming Yang
- Department of Anatomy, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Ce Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yi Zhou
- Department of Anatomy, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Peifeng Huang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xuezhen Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Lulu Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Liping Jiang
- Department of Parasitology, Xiangya School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410013, China
| | - Lidong Zhai
- Department of Anatomy, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Mingyu Yu
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Gong Cheng
- New Cornerstone Science Laboratory, Tsinghua University-Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, China; Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, 518132, China; Institute of Pathogenic Organisms, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518000, China; Southwest United Graduate School, Kunming, 650504, China.
| | - Long Yang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Research Center for Infectious Diseases, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; School of Public Health, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
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5
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Liu M, Guan W, Xie X, Li Z, Qiu G, Lin X, Xie Z, Zhang J, Qin Y, Huang Z, Xu X, Zhou C. Phase I Clinical Trial of Autologous Hematopoietic Stem Cell Transplantation-Supported Dose-Intensified Chemotherapy With Adebrelimab as First-Line Treatment for Extensive-Stage Small Cell Lung Cancer. Clin Lung Cancer 2025; 26:e236-e241. [PMID: 39848827 DOI: 10.1016/j.cllc.2024.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 12/26/2024] [Accepted: 12/26/2024] [Indexed: 01/25/2025]
Abstract
BACKGROUND Small cell lung cancer (SCLC) is initially highly sensitive to chemotherapy, which often leads to significant tumor reduction. However, the majority of patients eventually develop resistance, and the disease is further complicated by its "cold" tumor microenvironment, characterized by low tumor immunogenicity and limited CD8+ T cell infiltration. These factors contribute to the poor response to immunotherapy in many cases of extensive-stage SCLC (ES-SCLC). High-dose chemotherapy has shown potential in enhancing tumor cytoreduction, but its use is often limited by severe hematologic toxicity. Combining chemotherapy with immune checkpoint inhibitors (ICIs) can create a synergistic effect by promoting immunogenic cell death and enhancing immune activation. Autologous hematopoietic stem cell transplantation (auto-HSCT) provides a means to support hematopoietic recovery, mitigate chemotherapy-induced myelosuppression, and contribute to immune reconstitution. In this context, the integration of auto-HSCT with dose-intensified chemotherapy and ICIs aims to both protect the bone marrow and enhance antitumor immune responses, potentially overcoming resistance to immunotherapy in ES-SCLC. METHODS A phase I, single-center, single-arm trial was designed to evaluate the safety and efficacy of auto-HSCT-supported dose-intensified chemotherapy combined with adebrelimab in treatment-naive ES-SCLC patients. Participants will receive induction chemotherapy followed by stem cell mobilization, apheresis, and cryopreservation. After successful mobilization, consolidation chemotherapy with stem cell reinfusion and granulocyte colony-stimulating factor (G-CSF) support will be performed. Maintenance therapy with adebrelimab continues until disease progression or unacceptable toxicity. Safety and efficacy data, including adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), will be analyzed. RESULTS The study aims to enhance treatment outcomes by overcoming resistance to immuno-chemotherapy and promoting immune reconstitution. The trial is ongoing at the First Affiliated Hospital of Guangzhou Medical University. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT06597513.
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Affiliation(s)
- Ming Liu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenhui Guan
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaohong Xie
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zekun Li
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Guihuan Qiu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xinqing Lin
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhanhong Xie
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiexia Zhang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yinyin Qin
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhenqian Huang
- Department of Hematology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Xin Xu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Organ Transplantation, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Chengzhi Zhou
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Pulmonary and Critical Care Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
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6
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Ghaith AK, Yang X, Khalilullah T, Wang X, Alfonzo Horowitz M, Khalifeh J, Ahmed AK, Azad T, Weinberg J, Al-Mistarehi AH, Foster C, Bhimreddy M, Menta AK, Redmond KJ, Theodore N, Lubelski D. Histology-Specific Treatment Strategies and Survival Prediction in Lung Cancer Patients with Spinal Metastases: A Nationwide Analysis. Cancers (Basel) 2025; 17:1374. [PMID: 40282550 PMCID: PMC12025767 DOI: 10.3390/cancers17081374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND/OBJECTIVES Spinal metastases are a common and severe complication of lung cancer, particularly in small cell lung cancer (SCLC), and are associated with poor survival. Despite advancements in treatment, optimal management strategies remain unclear, with significant differences between non-small cell lung cancer (NSCLC) and SCLC. This study evaluates treatment patterns, survival outcomes, and prognostic factors in lung cancer patients with spinal metastases, integrating deep learning survival prediction models. METHODS This retrospective cohort study analyzed the National Cancer Database (NCDB) to identify NSCLC and SCLC patients diagnosed with spinal metastases. Demographics and treatment modalities were analyzed and adjusted for age, sex, and comorbidities. Kaplan-Meier analysis and Cox proportional hazards models assessed overall survival (OS). Five advanced survival prediction models estimated 1-year and 10-year mortality, with feature importance determined via permutation analysis. RESULTS Among 428,919 lung cancer patients, 5.1% developed spinal metastases, with a significantly higher incidence in SCLC (13.6%) than in NSCLC (5.1%). SCLC patients had poorer OS. Radiation therapy alone was the predominant treatment, and stereotactic body radiation therapy (SBRT) predicted better short- and long-term survival compared to other radiation techniques. High-dose radiation (71-150 Gy BED) improved OS in NSCLC, while reirradiation benefited NSCLC but had a limited impact in SCLC. SurvTrace demonstrated the highest predictive accuracy for 1-year and 10-year mortality, identifying age, radiation dose, reirradiation, and race as key prognostic factors. CONCLUSIONS The management of spinal metastases requires a histology-specific approach. Radiation remains the primary treatment, with SBRT predicting better short- and long-term survival. High-dose radiation and reirradiation should be considered for NSCLC, while the benefits are limited in SCLC. These findings support histology-specific treatment strategies to improve survival of patients with metastatic lung cancer to the spine.
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Affiliation(s)
- Abdul Karim Ghaith
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (A.K.G.); (X.Y.); (T.K.); (X.W.); (M.A.H.); (J.K.); (A.K.A.); (T.A.); (A.-H.A.-M.); (M.B.); (A.K.M.); (K.J.R.); (N.T.)
| | - Xinlan Yang
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (A.K.G.); (X.Y.); (T.K.); (X.W.); (M.A.H.); (J.K.); (A.K.A.); (T.A.); (A.-H.A.-M.); (M.B.); (A.K.M.); (K.J.R.); (N.T.)
| | - Taha Khalilullah
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (A.K.G.); (X.Y.); (T.K.); (X.W.); (M.A.H.); (J.K.); (A.K.A.); (T.A.); (A.-H.A.-M.); (M.B.); (A.K.M.); (K.J.R.); (N.T.)
| | - Xihang Wang
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (A.K.G.); (X.Y.); (T.K.); (X.W.); (M.A.H.); (J.K.); (A.K.A.); (T.A.); (A.-H.A.-M.); (M.B.); (A.K.M.); (K.J.R.); (N.T.)
| | - Melanie Alfonzo Horowitz
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (A.K.G.); (X.Y.); (T.K.); (X.W.); (M.A.H.); (J.K.); (A.K.A.); (T.A.); (A.-H.A.-M.); (M.B.); (A.K.M.); (K.J.R.); (N.T.)
| | - Jawad Khalifeh
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (A.K.G.); (X.Y.); (T.K.); (X.W.); (M.A.H.); (J.K.); (A.K.A.); (T.A.); (A.-H.A.-M.); (M.B.); (A.K.M.); (K.J.R.); (N.T.)
| | - A. Karim Ahmed
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (A.K.G.); (X.Y.); (T.K.); (X.W.); (M.A.H.); (J.K.); (A.K.A.); (T.A.); (A.-H.A.-M.); (M.B.); (A.K.M.); (K.J.R.); (N.T.)
| | - Tej Azad
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (A.K.G.); (X.Y.); (T.K.); (X.W.); (M.A.H.); (J.K.); (A.K.A.); (T.A.); (A.-H.A.-M.); (M.B.); (A.K.M.); (K.J.R.); (N.T.)
| | - Joshua Weinberg
- Department of Neurosurgery, School of Medicine, Ohio State University, Columbus, OH 43210, USA;
| | - Abdel-Hameed Al-Mistarehi
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (A.K.G.); (X.Y.); (T.K.); (X.W.); (M.A.H.); (J.K.); (A.K.A.); (T.A.); (A.-H.A.-M.); (M.B.); (A.K.M.); (K.J.R.); (N.T.)
| | - Chase Foster
- Department of Neurosurgery, School of Medicine, George Washington University, Washington, DC 20052, USA;
| | - Meghana Bhimreddy
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (A.K.G.); (X.Y.); (T.K.); (X.W.); (M.A.H.); (J.K.); (A.K.A.); (T.A.); (A.-H.A.-M.); (M.B.); (A.K.M.); (K.J.R.); (N.T.)
| | - Arjun K. Menta
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (A.K.G.); (X.Y.); (T.K.); (X.W.); (M.A.H.); (J.K.); (A.K.A.); (T.A.); (A.-H.A.-M.); (M.B.); (A.K.M.); (K.J.R.); (N.T.)
| | - Kristin J. Redmond
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (A.K.G.); (X.Y.); (T.K.); (X.W.); (M.A.H.); (J.K.); (A.K.A.); (T.A.); (A.-H.A.-M.); (M.B.); (A.K.M.); (K.J.R.); (N.T.)
| | - Nicholas Theodore
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (A.K.G.); (X.Y.); (T.K.); (X.W.); (M.A.H.); (J.K.); (A.K.A.); (T.A.); (A.-H.A.-M.); (M.B.); (A.K.M.); (K.J.R.); (N.T.)
| | - Daniel Lubelski
- Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; (A.K.G.); (X.Y.); (T.K.); (X.W.); (M.A.H.); (J.K.); (A.K.A.); (T.A.); (A.-H.A.-M.); (M.B.); (A.K.M.); (K.J.R.); (N.T.)
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7
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Das S, Zea MP, Russon MP, Xing Z, Torregrosa-Allen S, Cervantes HE, Harper HA, Elzey BD, Tran EJ. Supinoxin blocks small cell lung cancer progression by inhibiting mitochondrial respiration through DDX5. iScience 2025; 28:112219. [PMID: 40224004 PMCID: PMC11987007 DOI: 10.1016/j.isci.2025.112219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 12/26/2024] [Accepted: 03/11/2025] [Indexed: 04/15/2025] Open
Abstract
DDX5 is a DEAD-box RNA helicase that is overexpressed and implicated in the progression of several cancers, including small cell lung cancer (SCLC). Our laboratory has demonstrated that DDX5 is essential for the invasive growth of SCLC and mitochondrial respiration. SCLC is an extremely lethal, recalcitrant tumor, and currently lacking effective treatments. Supinoxin (RX 5902), a compound having anti-cancer activity, is a known target of phosphor-DDX5. We now report that Supinoxin inhibits the proliferation of chemo-sensitive and chemo-resistant SCLC lines, H69 and H69AR, respectively. Additionally, Supinoxin mitigates both the growth of H69AR xenograft tumors and SCLC PDX tumors in vivo. Finally, we find that Supinoxin inhibits expression of mitochondrial genes and effectively blocks respiration. These studies suggest that Supinoxin functions in anti-tumor progression by reducing cellular energy levels through DDX5.
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Affiliation(s)
- Subhadeep Das
- Department of Biochemistry, Purdue University, BCHM A343, 175 S. University Street, West Lafayette, IN 47907-2063, USA
- Purdue University Institute for Cancer Research, Purdue University, Hansen Life Sciences Research Building, Room 141, 201 S. University Street, West Lafayette, IN 47907-2064, USA
| | - Maria P. Zea
- Department of Biochemistry, Purdue University, BCHM A343, 175 S. University Street, West Lafayette, IN 47907-2063, USA
| | - Matthew P. Russon
- Department of Biochemistry, Purdue University, BCHM A343, 175 S. University Street, West Lafayette, IN 47907-2063, USA
| | - Zheng Xing
- Department of Biochemistry, Purdue University, BCHM A343, 175 S. University Street, West Lafayette, IN 47907-2063, USA
| | - Sandra Torregrosa-Allen
- Purdue University Institute for Cancer Research, Purdue University, Hansen Life Sciences Research Building, Room 141, 201 S. University Street, West Lafayette, IN 47907-2064, USA
| | - Heidi E. Cervantes
- Purdue University Institute for Cancer Research, Purdue University, Hansen Life Sciences Research Building, Room 141, 201 S. University Street, West Lafayette, IN 47907-2064, USA
| | - Haley Anne Harper
- Purdue University Institute for Cancer Research, Purdue University, Hansen Life Sciences Research Building, Room 141, 201 S. University Street, West Lafayette, IN 47907-2064, USA
| | - Bennett D. Elzey
- Purdue University Institute for Cancer Research, Purdue University, Hansen Life Sciences Research Building, Room 141, 201 S. University Street, West Lafayette, IN 47907-2064, USA
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA
| | - Elizabeth J. Tran
- Department of Biochemistry, Purdue University, BCHM A343, 175 S. University Street, West Lafayette, IN 47907-2063, USA
- Purdue University Institute for Cancer Research, Purdue University, Hansen Life Sciences Research Building, Room 141, 201 S. University Street, West Lafayette, IN 47907-2064, USA
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8
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Zhou JX, Sun YC, Xiao L, Lu HL, Yin XM, Fan K, Zhou YN. Efficacy analysis and prognostic factors of first-line chemotherapy combined with immunotherapy in extensive-stage small cell lung cancer: a real-world study. Sci Rep 2025; 15:13063. [PMID: 40240495 PMCID: PMC12003727 DOI: 10.1038/s41598-025-98018-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 04/08/2025] [Indexed: 04/18/2025] Open
Abstract
Extensive-stage small cell lung cancer (ES-SCLC) is a highly aggressive subtype of lung cancer with limited treatment options and poor prognosis. In recent years, immune checkpoint inhibitors (ICIs) combined with chemotherapy have demonstrated significant efficacy in several clinical trials. This study aims to evaluate the efficacy of first-line chemotherapy combined with immunotherapy in patients with ES-SCLC and identify prognostic factors based on real-world data. This retrospective study analyzed the clinical data of 349 patients with ES-SCLC treated at Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine from January 2018 to August 2023. The patients were divided into a combination group (chemotherapy plus immunotherapy, n = 173) and a chemotherapy group (chemotherapy alone, n = 176) based on their treatment regimens. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoint was treatment-related adverse events. Kaplan-Meier survival analysis was performed, and Cox regression models were used to analyze the factors influencing OS and PFS. The median OS in the combination group was 14.9 months, significantly longer than 11.9 months in the chemotherapy group (P < 0.001). After applying Propensity Score Matching (PSM) to minimize selection bias, the survival advantage remained statistically significant. The 1-, 2-, and 3-year OS rates in the combination group were 62.4%, 42.8%, and 19.5%, respectively, compared to 50.2%, 20.8%, and 9.6% in the chemotherapy group. The median PFS in the combination group was 5.4 months, also significantly longer than the 3.8 months observed in the chemotherapy group (P < 0.001). Multivariate analysis identified chemotherapy alone, ECOG performance status, and number of metastatic sites as independent risk factors for poorer OS and PFS (P < 0.001). A separate analysis was conducted to evaluate the association between tumor response (CR/PR/SD/PD) and survival outcomes, which showed that patients with CR/PR had significantly better OS and PFS compared to those with SD/PD (P < 0.001). These findings reinforce the clinical importance of achieving tumor response. There were no significant differences in the incidence of adverse events between the two groups, with most adverse events being grade 1-2, and no grade 5 adverse events were reported. This study demonstrates that chemotherapy combined with immunotherapy significantly prolongs OS and PFS in patients with ES-SCLC without substantially increasing treatment-related adverse events. This combination therapy shows promising clinical value for improving long-term prognosis in ES-SCLC patients. Future studies should explore potential biomarkers to optimize individualized treatment strategies.
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Affiliation(s)
- Jian-Xi Zhou
- Department of Radiation Oncology, Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine-Hebei Province, Cangzhou, 061000, Hebei, China
| | - Yun-Chuan Sun
- Department of Radiation Oncology, Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine-Hebei Province, Cangzhou, 061000, Hebei, China
| | - Li Xiao
- Department of Radiation Oncology, Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine-Hebei Province, Cangzhou, 061000, Hebei, China
| | - Hong-Ling Lu
- Department of Radiation Oncology, Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine-Hebei Province, Cangzhou, 061000, Hebei, China
| | - Xiao-Ming Yin
- Department of Radiation Oncology, Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine-Hebei Province, Cangzhou, 061000, Hebei, China
| | - Kui Fan
- Department of Radiation Oncology, Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine-Hebei Province, Cangzhou, 061000, Hebei, China
| | - Ying-Nan Zhou
- Department of Radiotherapy and Chemotherapy, Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine East Ward, Cangzhou, 061000, Hebei, China.
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9
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Dong H, Wang W. Role of radiotherapy on long-term outcomes of patients with small cell lung cancer under different metastasis patterns. World J Surg Oncol 2025; 23:125. [PMID: 40197230 PMCID: PMC11974141 DOI: 10.1186/s12957-025-03766-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 03/23/2025] [Indexed: 04/10/2025] Open
Abstract
OBJECTIVE Assessing the role of radiotherapy on the long-term outcomes in patients with small cell lung cancer (SCLC). METHODS A total of 6819 patients with SCLC diagnosed histologically from 2011 to 2020 were collected from the Surveillance, Epidemiology, and End Results database. The importance of radiation on overall survival (OS) and cancer-specific survival (CSS) was assessed by a random forest algorithm. The association of radiation with OS and CSS was evaluated by COX regression and subgroup analysis. The survival difference between radiation and non-radiation groups was analyzed by the Kaplan-Meier (KM) method. The conditional survival (CS) and competing risk analyses were performed to evaluate the influence of radiation on CSS. RESULTS Among all variables, the importance of tumor metastasis to OS and CSS ranked first. COX regression analysis indicated independent association (all P < 0.05) of radiation with OS and CSS in patients with metastasis in the liver, lymphatic, and other sites (not found in bone and brain). KM showed better OS and CSS in the radiation group (vs. non-radiation) in the 3 types of metastases (all P < 0.05). Among 5 metastasis patterns, liver metastasis (LM) was identified as the key pattern to OS and CSS. We found that LM patients with chemotherapy, female, and stage IV can significantly benefit from radiotherapy. However, radiation cannot decrease the incidence of cancer-specific death in male LM patients. CONCLUSIONS This study determined the importance of radiotherapy on the long-term outcomes of patients. In particular, male LM patients may not benefit from radiotherapy.
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Affiliation(s)
- Hui Dong
- Department of Respiratory, People's Hospital of Haining, Haining, Zhejiang, 314400, China.
| | - Wei Wang
- Department of General Surgery Three, People's Hospital of Haining, No.2 Qianjiang West Road, Haining, Zhejiang, 314400, China
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10
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Zhai X, Zhang Z, Chen Y, Wu Y, Zhen C, Liu Y, Lin Y, Chen C. Current and future therapies for small cell lung carcinoma. J Hematol Oncol 2025; 18:37. [PMID: 40170056 PMCID: PMC11959764 DOI: 10.1186/s13045-025-01690-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 03/14/2025] [Indexed: 04/03/2025] Open
Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid proliferation and high metastatic potential. It is characterized by universal inactivation of and RB1, overexpression of the MYC family and dysregulation of multiple oncogenic signaling pathways. Among different patients, SCLCs are similar at the genetic level but exhibit significant heterogeneity at the molecular level. The classification of SCLC has evolved from a simple neuroendocrine (NE)/non-neuroendocrine (non-NE) classification system to a transcription factor-based molecular subtype system; lineage plasticity adds further complexity and poses challenges for therapeutic development. While SCLC is initially sensitive to platinum-based chemotherapy, resistance develops rapidly, leading to a dismal prognosis. Various antibodies, including PD-1/PD-L1 inhibitors and antibody‒drug conjugates, have been introduced into clinical practice or are being evaluated in clinical trials. However, their therapeutic benefits for SCLC patients remain limited. This review summarizes SCLC carcinogenic mechanisms, tumor heterogeneity, and the immune microenvironment of SCLC, with a focus on recent advances in metastasis and resistance mechanisms. Additionally, the corresponding clinical progress in tackling these challenges is discussed.
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Affiliation(s)
- Xiaoqian Zhai
- Department of Medical Oncology, State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 1, Keyuan 4th Road, Gaopeng Avenue, Chengdu, 610041, Sichuan, China
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhengkun Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- College of Life Sciences, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yuxin Chen
- West China School of Medicine, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yanmou Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- College of Life Sciences, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Cheng Zhen
- West China School of Medicine, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yu Liu
- Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 1, Keyuan 4th Road, Gaopeng Avenue, Chengdu, 610041, Sichuan, China.
| | - Yiyun Lin
- Department of Medicine, Weill Cornell Medicine, East 69th Street, New York, NY, 10021, USA.
| | - Chong Chen
- Department of Medical Oncology, State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 1, Keyuan 4th Road, Gaopeng Avenue, Chengdu, 610041, Sichuan, China.
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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11
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Sun J, Zhang Z, Xia B, Yao T, Ge F, Yan F. Overexpression of PIK3CG in Cancer Cells Promotes Lung Cancer Cell Migration and Metastasis Through Enhanced MMPs Expression and Neutrophil Recruitment and Activation. Biochem Genet 2025; 63:1647-1659. [PMID: 38602596 DOI: 10.1007/s10528-024-10788-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 03/16/2024] [Indexed: 04/12/2024]
Abstract
Metastasis is a major cause of death in lung cancer. The aim of this study is to analyze the role and mechanism of PI3K catalytic subunit gamma (PIK3CG, also known as p110γ) in lung cancer cell migration and metastasis. Knockdown (KD) and overexpression (OE) of PIK3CG expression in lung cancer cell lines A549 and H1299 in vitro cultured was achieved. Two PIK3CG-specific inhibitors, Eganelisib and CAY10505, were used to treat A549 and H1299 cells. An experimental lung metastasis mouse model was constructed using tail vein injection of LLC cells. Finally, a co-culture system was established using Transwell chambers. Compared with the NC group, the number of cells that completed migration and the expression levels of matrix metalloproteinases (MMPs) were significantly reduced in the KD group and Eganelisib and CAY10505 treatment groups, while the number of cells that migrated successfully and the expression levels of MMPs were significantly increased in the OE group. Lung tissues of mice injected with PIK3CG-stabilized overexpressed LLC cells showed more pronounced lung cancer growth, lung metastatic nodules, neutrophil infiltration and MMPs expression. Co-culture with neutrophils, soluble extracts of neutrophils and cathepsin G all promoted the migration of lung cancer cells. PIK3CG overexpression in tumor cells significantly promoted the migration and metastasis of lung cancer cell.
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Affiliation(s)
- Jinpeng Sun
- Department of General Surgery Ward, Cangzhou Hospital of Integrated TCM-WM, No. 31 Yellow River West Road, Canal District, Cangzhou, 061000, Hebei, China.
| | - Zhenshan Zhang
- Department of Medical Oncology, Cangzhou Hospital of Integrated TCM-WM, Cangzhou, 061000, Hebei, China
| | - Binghui Xia
- Department of General Surgery Ward, Cangzhou Hospital of Integrated TCM-WM, No. 31 Yellow River West Road, Canal District, Cangzhou, 061000, Hebei, China
| | - Tianyu Yao
- Department of Cardiology, Cangzhou Hospital of Integrated TCM-WM, Cangzhou, 061000, Hebei, China
| | - Fengyue Ge
- Department of Function Laboratory, Cangzhou Hospital of Integrated TCM-WM, Cangzhou, 061000, Hebei, China
| | - Fengmei Yan
- Department of Endoscopic Diagnosis and Treatment Center, Cangzhou Hospital of Integrated TCM-WM, Cangzhou, 061000, Hebei, China
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12
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Sakamoto S, Inoue H, Takino T, Kohda Y, Yoshida J, Ohba S, Usami I, Suzuki T, Kawada M, Hatakeyama M. Claudin-11 Enhances Invasive and Metastatic Abilities of Small-Cell Lung Cancer Through MT1-MMP Activation. Cancer Sci 2025. [PMID: 40079504 DOI: 10.1111/cas.70038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 02/11/2025] [Accepted: 02/22/2025] [Indexed: 03/15/2025] Open
Abstract
Small-cell lung cancer (SCLC) is an aggressive tumor characterized by the frequent development of distant metastases. This study aimed to explore the mechanism of SCLC metastasis using an originally developed orthotopic transplantation model with DMS273 cells. An analysis of G3H cells, a highly metastatic subline of DMS273 cells, revealed that claudin-11 promotes the invasive and metastatic ability of the cells. Further analysis revealed that membrane type 1-matrix metalloproteinase (MT1-MMP), which degrades a wide range of extracellular matrix components, was coprecipitated with claudin-11. Gelatin zymography revealed that claudin-11 enhanced MT1-MMP activity, and MT1-MMP silencing suppressed the invasive and metastatic ability of G3H cells. Moreover, in MT1-MMP silencing DMS273 cells, the enhancement of invasion and metastatic potential induced by CLDN11 overexpression was abolished. These results demonstrate that claudin-11 enhances the invasive capacity of the cells by activating MT1-MMP, which promotes metastatic formation in the orthotopic transplantation model. Additionally, claudin-11 expression was detected in SCLC tumor samples, and higher expression of CLDN11 correlated with poor prognosis in patients with SCLC. These findings suggest that the claudin-11/MT1-MMP axis plays an important role in SCLC pathogenesis.
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Affiliation(s)
- Shuichi Sakamoto
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu, Japan
| | - Hiroyuki Inoue
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu, Japan
| | - Takahisa Takino
- Institute of Liberal Arts & Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yasuko Kohda
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu, Japan
| | - Junjiro Yoshida
- Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, Microbial Chemistry Research Foundation, Tokyo, Japan
| | - Shunichi Ohba
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu, Japan
| | - Ihomi Usami
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu, Japan
| | - Takeshi Suzuki
- Division of Functional Genomics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Manabu Kawada
- Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, Microbial Chemistry Research Foundation, Tokyo, Japan
| | - Masanori Hatakeyama
- Institute of Microbial Chemistry (BIKAKEN), Laboratory of Microbial Carcinogenesis, Microbial Chemistry Research Foundation, Tokyo, Japan
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13
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Zhang S, Zhang Y, Feng S, Han M, Wang Z, Qiao D, Tian J, Wang L, Du B, Zhang Z, Zhong J. Tumor-promoting effect and tumor immunity of SRSFs. Front Cell Dev Biol 2025; 13:1527309. [PMID: 40129567 PMCID: PMC11931056 DOI: 10.3389/fcell.2025.1527309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/17/2025] [Indexed: 03/26/2025] Open
Abstract
Serine/arginine-rich splicing factors (SRSFs) are a family of 12 RNA-binding proteins crucial for the precursor messenger RNA (pre-mRNA) splicing. SRSFs are involved in RNA metabolism events such as transcription, translation, and nonsense decay during the shuttle between the nucleus and cytoplasm, which are important components of genome diversity and cell viability. SRs recognize splicing elements on pre-mRNA and recruit the spliceosome to regulate splicing. In tumors, aberrant expression of SRSFs leads to aberrant splicing of RNA, affecting the proliferation, migration, and anti-apoptotic ability of tumor cells, highlighting the therapeutic potential of targeted SRSFs for the treatment of diseases. The body's immune system is closely related to the occurrence and development of tumor, and SRSFs can affect the function of immune cells in the tumor microenvironment by regulating the alternative splicing of tumor immune-related genes. We review the important role of SRSFs-induced aberrant gene expression in a variety of tumors and the immune system, and prospect the application of SRSFs in tumor. We hope that this review will inform future treatment of the disease.
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Affiliation(s)
- Shuai Zhang
- Department of Oncology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Yongxi Zhang
- Department of Oncology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Sijia Feng
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Miaomiao Han
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Zixi Wang
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Dan Qiao
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Jiaqi Tian
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Lan Wang
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Baoshun Du
- Second Department of Neurosurgery, Xinxiang Central Hospital, Xinxiang, China
| | - Zheying Zhang
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Jiateng Zhong
- Department of Oncology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
- Henan Province Engineering Technology Research Center of Tumor diagnostic biomarkers and RNA interference drugs, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
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14
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Skurikhin EG, Ermakova NN, Zhukova MA, Pan ES, Kubatiev AA, Morozov SG, Dygai AM. In Vitro Study of Cancer Stem Cells and Reprogrammed CD3 +CD8 + T Cells: the Search for Personalized Diagnostics and Targeted Treatment of Small Cell Lung Cancer (Experience of a Pilot Study). Bull Exp Biol Med 2025; 178:631-636. [PMID: 40293593 DOI: 10.1007/s10517-025-06388-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Indexed: 04/30/2025]
Abstract
The content of cancer stem cells and CD3+CD8+ T cells in the blood of a patient with small cell lung cancer (SCLC) and chronic obstructive pulmonary disease (COPD) was evaluated. In vitro analysis of tumorospheres allowed us to characterize circulating tumor stem cells in the blood of patients at risk. The fundamental possibility of reprogramming exhausted CD3+CD8+ T cells (rCD3CD8T) of a patient with SCLC and COPD using a mitogen-activated protein kinase inhibitor (iMEK) and human monoclonal antibody nivolumab was demonstrated. Target cell elimination by rCD3CD8T was achieved by treatment with autologous cancer cell and stem cancer cell lysate in vitro. Thus, blockade of the MAPK/ERK signaling pathway and the PD-1/PD-L1 checkpoints may be used to overcome exhaustion and enhance cytotoxicity of CD3+CD8+ T cells in patients with SCLC and COPD.
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Affiliation(s)
- E G Skurikhin
- Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - N N Ermakova
- Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - M A Zhukova
- Institute of General Pathology and Pathophysiology, Moscow, Russia.
| | - E S Pan
- Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - A A Kubatiev
- Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - S G Morozov
- Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - A M Dygai
- Institute of General Pathology and Pathophysiology, Moscow, Russia
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15
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Deng X, Wang Y, Yang X, Yu Q, Huang R, Chen H, Li W, He Y. Synthesis, Structural Modification, and Antismall Cell Lung Cancer Activity of 3-Arylisoquinolines with Dual Inhibitory Activity on Topoisomerase I and II. J Med Chem 2025; 68:3518-3546. [PMID: 39844445 DOI: 10.1021/acs.jmedchem.4c02689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
To overcome the compensatory effect between Topo I and II, one of the reasons accounting for the resistance of SCLC patients, we are pioneering the use of 3-arylisoquinolines to develop dual inhibitors of Topo I/II for the management of SCLC. A total of 46 new compounds were synthesized. Compounds 3g (IC50 = 1.30 μM for NCI-H446 cells and 1.42 μM for NCI-H1048 cells) and 3x (IC50 = 1.32 μM for NCI-H446 cells and 2.45 μM for NCI-H1048 cells) were selected for detailed pharmacological investigation, due to their outstanding cytotoxicity and dual Topo I and II inhibitory activity. 3g and 3x effectively prevent SCLC cell proliferation, invasion, and migration in vitro, byinducing mitochondrial apoptosis and inhibiting the PI3K/Akt/mTOR pathway. Their in vivo tumor inhibition rate is comparable to etoposide with lower toxicity. These results indicated their potential therapeutic values as dual Topo I and II inhibitors for treating SCLC.
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Affiliation(s)
- Xuemei Deng
- Department of Respiratory and Critical Care Medicine, Molecularly Targeted Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Molecularly Targeted Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
| | - Yuying Wang
- Department of Respiratory and Critical Care Medicine, Molecularly Targeted Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Molecularly Targeted Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
| | - Xiongqi Yang
- Department of Respiratory and Critical Care Medicine, Molecularly Targeted Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Molecularly Targeted Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
| | - Quanwei Yu
- Department of Respiratory and Critical Care Medicine, Molecularly Targeted Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Molecularly Targeted Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
| | - Ridong Huang
- Department of Respiratory and Critical Care Medicine, Molecularly Targeted Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Molecularly Targeted Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
| | - Hai Chen
- Department of Respiratory and Critical Care Medicine, Molecularly Targeted Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Molecularly Targeted Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
| | - Weimin Li
- Department of Respiratory and Critical Care Medicine, Molecularly Targeted Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Molecularly Targeted Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
| | - Yang He
- Department of Respiratory and Critical Care Medicine, Molecularly Targeted Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Molecularly Targeted Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
- State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China
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16
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Yang J, Luo Y, Yao Z, Wang Z, Jiang K. Theoretical perspectives and clinical applications of non-coding RNA in lung cancer metastasis: a systematic review. Discov Oncol 2025; 16:169. [PMID: 39937377 PMCID: PMC11822152 DOI: 10.1007/s12672-025-01919-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 02/04/2025] [Indexed: 02/13/2025] Open
Abstract
Lung cancer is one of the deadliest malignancies worldwide, with distant metastasis being a major cause of death. However, the specific mechanisms of lung cancer metastasis remain unclear. NcRNAs, a widely present type of non-coding RNAs in the body, constitute about 98% of the human genome, lacking protein-coding capacity but involved in various cellular processes such as proliferation, apoptosis, invasion, and migration. Studies have shown that ncRNAs play a crucial role in the metastasis of lung cancer, although research in this area is limited. This review summarizes the biological origins and functions of ncRNAs, their specific roles and mechanisms in lung cancer metastasis, and discusses their potential for early screening and therapeutic applications in lung cancer. Furthermore, it outlines the challenges in translating basic advancements of ncRNAs in lung cancer metastasis into clinical practice.
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Affiliation(s)
- Jie Yang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, People's Republic of China
| | - Yi Luo
- The Clinical Medical College, Guizhou Medical University, Guiyang, 550004, People's Republic of China
| | - Zuhuan Yao
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, People's Republic of China
| | - Zhaokai Wang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, People's Republic of China
| | - Ke Jiang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, People's Republic of China.
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17
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Torre-Cea I, Berlana-Galán P, Guerra-Paes E, Cáceres-Calle D, Carrera-Aguado I, Marcos-Zazo L, Sánchez-Juanes F, Muñoz-Félix JM. Basement membranes in lung metastasis growth and progression. Matrix Biol 2025; 135:135-152. [PMID: 39719224 DOI: 10.1016/j.matbio.2024.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/19/2024] [Accepted: 12/20/2024] [Indexed: 12/26/2024]
Abstract
The lung is a highly vascularized tissue that often harbors metastases from various extrathoracic malignancies. Lung parenchyma consists of a complex network of alveolar epithelial cells and microvessels, structured within an architecture defined by basement membranes. Consequently, understanding the role of the extracellular matrix (ECM) in the growth of lung metastases is essential to uncover the biology of this pathology and developing targeted therapies. These basement membranes play a critical role in the progression of lung metastases, influencing multiple stages of the metastatic cascade, from the acquisition of an aggressive phenotype to intravasation, extravasation and colonization of secondary sites. This review examines the biological composition of basement membranes, focusing on their core components-collagens, fibronectin, and laminin-and their specific roles in cancer progression. Additionally, we discuss the function of integrins as primary mediators of cell adhesion and signaling between tumor cells, basement membranes and the extracellular matrix, as well as their implications for metastatic growth in the lung. We also explore vascular co-option (VCO) as a form of tumor growth resistance linked to basement membranes and tumor vasculature. Finally, the review covers current clinical therapies targeting tumor adhesion, extracellular matrix remodeling, and vascular development, aiming to improve the precision and effectiveness of treatments against lung metastases.
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Affiliation(s)
- Irene Torre-Cea
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Spain
| | - Patricia Berlana-Galán
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Spain
| | - Elena Guerra-Paes
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Spain
| | - Daniel Cáceres-Calle
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Spain
| | - Iván Carrera-Aguado
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Spain
| | - Laura Marcos-Zazo
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Spain
| | - Fernando Sánchez-Juanes
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Spain.
| | - José M Muñoz-Félix
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Spain.
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18
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Li H, Wu F, Han Y, Guo Z, Chen T, Ma Z. CircRNA regulates lung cancer metastasis. Gene 2025; 935:149060. [PMID: 39481770 DOI: 10.1016/j.gene.2024.149060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/11/2024] [Accepted: 10/28/2024] [Indexed: 11/02/2024]
Abstract
Lung cancer stands prominently among the foremost contributors to human mortality, distinguished by its elevated fatality rate and the second-highest incidence rate among malignancies. The metastatic dissemination of lung cancer stands as a primary determinant of its elevated mortality and recurrence rates, underscoring the imperative for comprehensive investigation into its metastatic pathways. Circular RNAs (circRNAs), a subclass of non-coding RNA (ncRNA) molecules, have garnered attention for their pivotal involvement in the genesis and advancement of lung cancer. Emerging evidence highlights the indispensable functions of circRNAs in orchestrating the metastatic cascade of lung cancer. This review primarily discusses the mechanisms by which circRNAs act as competitive endogenous RNAs (ceRNAs) and modulate various signaling pathways to regulate lung cancer metastasis. CircRNAs influence critical cellular processes including angiogenesis, autophagy, and glycolysis, thereby exerting influence over the metastatic cascade in lung cancer. These discoveries offer innovative perspectives and therapeutic avenues for the diagnosis and management of lung cancer.
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Affiliation(s)
- Han Li
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, 381 Nanchen Road, Shanghai 200444, China
| | - Fan Wu
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, 381 Nanchen Road, Shanghai 200444, China
| | - Yaqi Han
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, 381 Nanchen Road, Shanghai 200444, China
| | - Ziyi Guo
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, 381 Nanchen Road, Shanghai 200444, China
| | - Tangbing Chen
- Department of Thoracic Surgery, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
| | - Zhongliang Ma
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, 381 Nanchen Road, Shanghai 200444, China.
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19
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Kwiecień I, Rutkowska E, Raniszewska A, Sokołowski R, Bednarek J, Jahnz-Różyk K, Rzepecki P. The Detection of Lung Cancer Cell Profiles in Mediastinal Lymph Nodes Using a Hematological Analyzer and Flow Cytometry Method. Cancers (Basel) 2025; 17:431. [PMID: 39941799 PMCID: PMC11816154 DOI: 10.3390/cancers17030431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/16/2025] [Accepted: 01/24/2025] [Indexed: 02/16/2025] Open
Abstract
The presence of metastases in mediastinal lymph nodes (LNs) is essential for planning lung cancer treatment and assessing anticancer immune responses. The aim of the study was to assess LNs for the presence of neoplastic cells and evaluate lung cancer-selected antigen expression. LN aspirates were obtained during an EBUS/TBNA procedure. The cells were analyzed using a hematological analyzer and flow cytometry. It was possible to indicate the presence of cells characterized by high fluorescence connected with high metabolic activity using a hematological analyzer and to determine their non-hematopoietic origin using flow cytometry. Using these methods together, we detected very quickly a high proportion of cancer cells in LNs. We noticed that it was possible to determine a high expression of EpCAM, TTF-1, Ki67, cytokeratin, HER, and differences between non-small-cell (NSCLC) and small-cell lung cancer (SCLC) for the antigens MUC-1, CD56, HLA-DR, CD39, CD184, PD-L1, PD-L2 and CTLA-4 on tumor cells. We report, for the first time, that the detection of tumor cells in LNs with the expression of specific antigens is easy to evaluate using a hematological analyzer and flow cytometry in EBUS/TBNA samples. Such precise characteristics of non-hematopoietic cells in LNs may be of great diagnostic importance in the detection of micrometastases.
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Affiliation(s)
- Iwona Kwiecień
- Laboratory of Hematology and Flow Cytometry, Department of Internal Medicine and Hematology, Military Institute of Medicine—National Research Institute, 04-141 Warsaw, Poland; (E.R.); (A.R.)
| | - Elżbieta Rutkowska
- Laboratory of Hematology and Flow Cytometry, Department of Internal Medicine and Hematology, Military Institute of Medicine—National Research Institute, 04-141 Warsaw, Poland; (E.R.); (A.R.)
| | - Agata Raniszewska
- Laboratory of Hematology and Flow Cytometry, Department of Internal Medicine and Hematology, Military Institute of Medicine—National Research Institute, 04-141 Warsaw, Poland; (E.R.); (A.R.)
| | - Rafał Sokołowski
- Department of Internal Medicine, Pneumonology, Allergology, Clinical Immunology and Rare Diseases, Military Institute of Medicine—National Research Institute, 04-141 Warsaw, Poland; (R.S.); (J.B.); (K.J.-R.)
| | - Joanna Bednarek
- Department of Internal Medicine, Pneumonology, Allergology, Clinical Immunology and Rare Diseases, Military Institute of Medicine—National Research Institute, 04-141 Warsaw, Poland; (R.S.); (J.B.); (K.J.-R.)
| | - Karina Jahnz-Różyk
- Department of Internal Medicine, Pneumonology, Allergology, Clinical Immunology and Rare Diseases, Military Institute of Medicine—National Research Institute, 04-141 Warsaw, Poland; (R.S.); (J.B.); (K.J.-R.)
| | - Piotr Rzepecki
- Department of Internal Medicine and Hematology, Military Institute of Medicine—National Research Institute, 04-141 Warsaw, Poland;
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20
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Krishnamurthy M, Dhall A, Sahoo S, Schultz CW, Baird MA, Desai P, Odell J, Takahashi N, Nirula M, Zhuang S, Huang Y, Schroeder B, Zhang Y, Thomas MS, Redon C, Robinson C, Thang L, Ileva L, Patel NL, Kalen JD, Varlet AA, Zuela-Sopilniak N, Jha A, Wangsa D, Butcher D, Morgan T, Afzal AN, Chari R, Baktiar K, Kumar S, Pongor L, Difilippantonio S, Aladjem MI, Pommier Y, Jolly MK, Lammerding J, Sharma AK, Thomas A. Metastatic organotropism in small cell lung cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.10.07.617066. [PMID: 39416100 PMCID: PMC11483079 DOI: 10.1101/2024.10.07.617066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Metastasis is the leading cause of cancer-related deaths, yet its regulatory mechanisms are not fully understood. Small-cell lung cancer (SCLC) is the most metastatic form of lung cancer, with most patients presenting with widespread disease, making it an ideal model for studying metastasis. However, the lack of suitable preclinical models has limited such studies. We utilized rapid autopsy-derived tumors to develop xenograft models that mimic key features of SCLC, including histopathology, rapid and widespread development of metastasis to the liver, brain, adrenal, bone marrow, and kidneys within weeks, and response to chemotherapy. By integrating in vivo lineage selection with comprehensive bulk and single cell multiomic profiling of transcriptomes and chromatin accessibility, we identified critical cellular programs driving metastatic organotropism to the liver and brain, the most common sites of SCLC metastasis. Our findings reveal the key role of nuclear-cytoskeletal interactions in SCLC liver metastasis. Specifically, the loss of the nuclear envelope protein lamin A/C, encoded by the LMNA gene, increased nuclear deformability and significantly increased the incidence of liver metastasis. Human liver metastases exhibited reduced LMNA expression compared to other metastatic sites, correlating with poorer patient outcomes and increased mortality. This study introduces novel preclinical models for SCLC metastasis and highlights pathways critical for organ-specific metastasis, offering new avenues for the development of targeted therapies to prevent or treat metastatic disease.
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Affiliation(s)
- Manan Krishnamurthy
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
- Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Anjali Dhall
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Sarthak Sahoo
- Department of Bioengineering, Indian Institute of Science, Bangalore, India
| | - Christopher W. Schultz
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Michelle A. Baird
- Cell and Developmental Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health; Bethesda, USA
| | - Parth Desai
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
- Department of Hematology & Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA
| | - Jacob Odell
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA; Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA; Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Nobuyuki Takahashi
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
- Department of Medical Oncology, National Cancer Center East Hospital, Kashiwa, Japan
| | - Michael Nirula
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Sophie Zhuang
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Yue Huang
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Brett Schroeder
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Yang Zhang
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Maria Sebastian Thomas
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Christophe Redon
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Christina Robinson
- Animal Research Technical Support, Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, NIH, Frederick, MD 21701
| | - Lai Thang
- Animal Research Technical Support, Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, NIH, Frederick, MD 21701
| | - Lilia Ileva
- Small Animal Imaging Program, Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Nimit L. Patel
- Small Animal Imaging Program, Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Joseph D. Kalen
- Small Animal Imaging Program, Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Alice-Anaïs Varlet
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA; Graduate Field of Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853, USA
| | - Noam Zuela-Sopilniak
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA; Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Ankita Jha
- Cell and Developmental Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health; Bethesda, USA
| | - Darawalee Wangsa
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Donna Butcher
- Molecular Histopathology Laboratory, Laboratory of Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Tamara Morgan
- Molecular Histopathology Laboratory, Laboratory of Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Alyah N. Afzal
- Laboratory Animal Sciences Program, Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, USA
| | - Raj Chari
- Laboratory Animal Sciences Program, Genome Modification Core, Frederick National Laboratory for Cancer Research, Frederick, USA
| | - Karim Baktiar
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Suresh Kumar
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Lorinc Pongor
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
- Cancer Genomics and Epigenetics Core Group, Szeged, Hungary
| | - Simone Difilippantonio
- Animal Research Technical Support, Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, NIH, Frederick, MD 21701
| | - Mirit I. Aladjem
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Yves Pommier
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Mohit Kumar Jolly
- Department of Bioengineering, Indian Institute of Science, Bangalore, India
| | - Jan Lammerding
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA; Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Ajit Kumar Sharma
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Anish Thomas
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
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21
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Cáceres-Calle D, Torre-Cea I, Marcos-Zazo L, Carrera-Aguado I, Guerra-Paes E, Berlana-Galán P, Muñoz-Félix JM, Sánchez-Juanes F. Integrins as Key Mediators of Metastasis. Int J Mol Sci 2025; 26:904. [PMID: 39940673 PMCID: PMC11816423 DOI: 10.3390/ijms26030904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/16/2025] [Accepted: 01/20/2025] [Indexed: 02/16/2025] Open
Abstract
Metastasis is currently becoming a major clinical concern, due to its potential to cause therapeutic resistance. Its development involves a series of phases that describe the metastatic cascade: preparation of the pre-metastatic niche, epithelial-mesenchymal transition, dissemination, latency and colonization of the new tissue. In the last few years, new therapeutic targets, such as integrins, are arising to face this disease. Integrins are transmembrane proteins found in every cell that have a key role in the metastatic cascade. They intervene in adhesion and intracellular signaling dependent on the extracellular matrix and cytokines found in the microenvironment. In this case, integrins can initiate the epithelial-mesenchymal transition, guide the formation of the pre-metastatic niche and increase tumor migration and survival. Integrins also take part in the tumor vascularization process necessary to sustain metastasis. This fact emphasizes the importance of inhibitory therapies capable of interfering with the function of integrins in metastasis.
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Affiliation(s)
- Daniel Cáceres-Calle
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain; (D.C.-C.); (I.T.-C.); (L.M.-Z.); (I.C.-A.); (E.G.-P.); (P.B.-G.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Irene Torre-Cea
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain; (D.C.-C.); (I.T.-C.); (L.M.-Z.); (I.C.-A.); (E.G.-P.); (P.B.-G.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Laura Marcos-Zazo
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain; (D.C.-C.); (I.T.-C.); (L.M.-Z.); (I.C.-A.); (E.G.-P.); (P.B.-G.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Iván Carrera-Aguado
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain; (D.C.-C.); (I.T.-C.); (L.M.-Z.); (I.C.-A.); (E.G.-P.); (P.B.-G.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Elena Guerra-Paes
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain; (D.C.-C.); (I.T.-C.); (L.M.-Z.); (I.C.-A.); (E.G.-P.); (P.B.-G.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Patricia Berlana-Galán
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain; (D.C.-C.); (I.T.-C.); (L.M.-Z.); (I.C.-A.); (E.G.-P.); (P.B.-G.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - José M. Muñoz-Félix
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain; (D.C.-C.); (I.T.-C.); (L.M.-Z.); (I.C.-A.); (E.G.-P.); (P.B.-G.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Fernando Sánchez-Juanes
- Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, 37007 Salamanca, Spain; (D.C.-C.); (I.T.-C.); (L.M.-Z.); (I.C.-A.); (E.G.-P.); (P.B.-G.)
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
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22
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Zhang J, Li H, Zhang X, Yang Y, Sun Y. The landscape of immunogenic cell death-related genes predicts the overall survival and immune infiltration status of non-small-cell lung carcinoma. Heliyon 2025; 11:e40869. [PMID: 39834423 PMCID: PMC11745784 DOI: 10.1016/j.heliyon.2024.e40869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 11/27/2024] [Accepted: 12/01/2024] [Indexed: 01/22/2025] Open
Abstract
Background Non-small cell lung cancer (NSCLC), which accounts for about 85 % of all lung cancers, currently exhibits insensitivity to most treatment regimens. Therefore, the identification of new and effective biomarkers for NSCLC is crucial for the development of treatment strategies. Immunogenic cell death (ICD), a form of regulated cell death capable of activating adaptive immune responses and generating long-term immune memory, holds promise for enhancing anti-tumor immunity and offering promising prospects for immunotherapy strategies in NSCLC. Methods Clinical information and expressive profiles of NSCLC genes were retrieved from the GEO and TCGA databases. By combining these databases, the researchers were able to identify the appropriate genes for use in forecasting outcomes of patients with this type of cancer. We further performed functional enrichment, gene variants and immune privilege correlation analysis to determine the underlying mechanisms. This was followed by univariate and multivariate Cox regression and LASSO regression analyses, we developed a prognostic risk model based on the TCGA cohort, which included 17 gene labels. The results of the external validation were then used to identify the appropriate genes for use in predicting the survival outcome of patients with this type of cancer. In addition, a nomogram was created to help visualise the clinical presentation of the patients. For the analyses, we performed 50 functional and immunoinfiltration assessments for two risk groups. Results Using 17 genes (AIRE, APOH, CDKN2A, CEACAM4, COL4A3, CPA, DBH, F10, FCGRB, FGFR4, MMP1, PGLYRP1, SCGB2A2, SLC9A3, UGT2B17 and VIP), The researchers then created a gene signature that could be used to identify patients with an increased risk of contracting cancer. They divided the patients into two groups based on their risk score. The low-risk group exhibited a better prognosis (P < 0.01). The survival curve demonstrated that ICD-related models could accurately predict patient prognosis. Conversely, high-risk subgroups were closely associated with immune-related signaling pathways. The analysis of immune infiltration also showed that the infiltration levels of most immune cells were higher in the high risk sub-group than in the low risk sub-group. In comparison to the low-risk group, the high-risk group was more susceptible to the immune-checkpoint blockade (ICB) treatment. Conclusion Our researchers utilized a gene model to analyze the immune inflammation and prognosis of patients with non-small-cell lung cancer (NSCLC). The discovery of new ICD-related genes could lead to the development of new targeted treatments for this condition.
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Affiliation(s)
- Jian Zhang
- Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, Heilongjiang, China
| | - Huiying Li
- Department of Pathology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, Heilongjiang, China
| | - Xi Zhang
- Department of Pathology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, Heilongjiang, China
| | - Yue Yang
- Institute of cancer prevention and treatment, Harbin Medical University, 6 Baojian Road, Harbin, 150000, Heilongjiang, China
| | - Yue Sun
- Science and Technology Academic Department of Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, Heilongjiang, China
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Hao Y, Li M, Liu W, Ma Z, Liu Z. Autophagic flux modulates tumor heterogeneity and lineage plasticity in SCLC. Front Oncol 2025; 14:1509183. [PMID: 39850810 PMCID: PMC11754400 DOI: 10.3389/fonc.2024.1509183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 12/12/2024] [Indexed: 01/25/2025] Open
Abstract
Introduction Small cell lung cancer (SCLC) is characterized by significant heterogeneity and plasticity, contributing to its aggressive progression and therapy resistance. Autophagy, a conserved cellular process, is implicated in many cancers, but its role in SCLC remains unclear. Methods Using a genetically engineered mouse model (Rb1fl/fl ; Trp53fl/fl ; GFP-LC3-RFP-LC3△G), we tracked autophagic flux in vivo to investigate its effects on SCLC biology. Additional in vitro experiments were conducted to modulate autophagic flux in NE and non-NE SCLC cell lines. Results Tumor subpopulations with high autophagic flux displayed increased proliferation, enhanced metastatic potential, and neuroendocrine (NE) characteristics. Conversely, low-autophagic flux subpopulations exhibited immune-related signals and non-NE traits. In vitro, increasing autophagy induced NE features in non-NE cell lines, while autophagy inhibition in NE cell lines promoted non-NE characteristics. Discussion This study provides a novel model for investigating autophagy in vivo and underscores its critical role in driving SCLC heterogeneity and plasticity, offering potential therapeutic insights.
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Affiliation(s)
- Yujie Hao
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Mingchen Li
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Wenxu Liu
- Zhejiang Key Laboratory of Medical Epigenetics, Department of Cell Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Zhenyi Ma
- Zhejiang Key Laboratory of Medical Epigenetics, Department of Cell Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Zhe Liu
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
- Zhejiang Key Laboratory of Medical Epigenetics, Department of Cell Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
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24
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Rao JH, Zha CP, Zhang WD, Cheng LH, Lei Q, Xie T, Peng W, Ye PJ, Zhang MY, Xing YJ, Sun CZ, Li L. Cervical Lymph Nodes Metastasis From Non-head and Neck Primary Carcinomas: A Retrospective Analysis of 1448 Patients. Head Neck 2025; 47:400-409. [PMID: 39545349 DOI: 10.1002/hed.28002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 10/21/2024] [Accepted: 11/04/2024] [Indexed: 11/17/2024] Open
Abstract
OBJECTIVE To investigate the clinicopathological features of individuals who have cervical lymph node metastasis (CLNM) from non-head and neck primary carcinomas. METHODS The data of 1448 patients diagnosed with CLNM from non-head and neck primary carcinomas at the Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, China, from January 2013 to December 2023 were collected. The patients' general information, imaging data, and pathological information were retrospectively analyzed. RESULTS There were 780 men and 668 women among the 1448 patients, for a male-to-female ratio of 1.17:1. The median age was 56 years (range 21-81 years). The most prevalent primary sites in males were the lung (n = 508, 65.1%) and, in females, the breast (n = 276, 41.3%). The most prevalent pathological kind (n = 949), or 65.5% of cases, was adenocarcinoma. There was a significant difference in the proportion of adenocarcinoma between males (n = 385, 49.4%) and females (n = 564, 84.4%). The common sites of CLNM from non-head and neck primary carcinomas were level V (1,236 cases, 85.4%). In a subgroup of 1133 patients with primary cancer located in symmetrical or unilateral organs, 60.3% exhibited ipsilateral lymph node metastasis, 27.6% had bilateral lymph node metastasis, and 12.1% showed contralateral lymph node metastasis exclusively. CONCLUSION For patients with CLNM, especially those with metastasis to cervical areas IV-V and those with adenocarcinoma pathology, it is particularly important to screen for primary foci in the lungs, breast, urogenital system, and digestive system after excluding head and neck primary cancers.
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Affiliation(s)
- Jin-Hui Rao
- Department of Head and Neck Surgery Section II, the Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Cheng-Peng Zha
- Department of Head and Neck Surgery Section II, the Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Wen-Da Zhang
- Department of Head and Neck Surgery Section II, the Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Liu-Han Cheng
- Department of Head and Neck Surgery Section II, the Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Qian Lei
- Department of Head and Neck Surgery Section II, the Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Tao Xie
- Department of Head and Neck Surgery Section II, the Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Wen Peng
- Department of Head and Neck Surgery Section II, the Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Pei-Jing Ye
- Department of Head and Neck Surgery Section II, the Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Min-Yue Zhang
- Department of Head and Neck Surgery Section II, the Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yu-Jie Xing
- Department of Head and Neck Surgery Section II, the Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chuan-Zheng Sun
- Department of Head and Neck Surgery Section II, the Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lei Li
- Department of Head and Neck Surgery Section II, the Yunnan Cancer Hospital, Third Affiliated Hospital of Kunming Medical University, Kunming, China
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Behrouzi R, Clipson A, Simpson KL, Blackhall F, Rothwell DG, Dive C, Mouliere F. Cell-free and extrachromosomal DNA profiling of small cell lung cancer. Trends Mol Med 2025; 31:64-78. [PMID: 39232927 DOI: 10.1016/j.molmed.2024.08.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/09/2024] [Accepted: 08/12/2024] [Indexed: 09/06/2024]
Abstract
Small cell lung cancer (SCLC) is highly aggressive with poor prognosis. Despite a relative prevalence of circulating tumour DNA (ctDNA) in SCLC, liquid biopsies are not currently implemented, unlike non-SCLC where cell-free DNA (cfDNA) mutation profiling in the blood has utility for guiding targeted therapies and assessing minimal residual disease. cfDNA methylation profiling is highly sensitive for SCLC detection and holds promise for disease monitoring and molecular subtyping; cfDNA fragmentation profiling has also demonstrated clinical potential. Extrachromosomal DNA (ecDNA), that is often observed in SCLC, promotes tumour heterogeneity and chemotherapy resistance and can be detected in blood. We discuss how these cfDNA profiling modalities can be harnessed to expand the clinical applications of liquid biopsy in SCLC.
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Affiliation(s)
- Roya Behrouzi
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, UK; Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
| | - Alexandra Clipson
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, UK
| | - Kathryn L Simpson
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, UK; Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
| | - Fiona Blackhall
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, UK
| | - Dominic G Rothwell
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, UK
| | - Caroline Dive
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, UK; Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK
| | - Florent Mouliere
- Cancer Research UK National Biomarker Centre, University of Manchester, Manchester, UK.
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Moyana TN. Small cell lung carcinoma metastatic to the stomach: Commonly overlooked, limited treatment options. World J Gastroenterol 2024; 30:5198-5204. [PMID: 39735276 PMCID: PMC11612703 DOI: 10.3748/wjg.v30.i48.5198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/23/2024] [Accepted: 11/13/2024] [Indexed: 11/29/2024] Open
Abstract
Small cell lung carcinoma metastatic to the stomach, whether synchronous or metachronous, is a rare phenomenon accounting for < 0.5% of lung cancers. Hence it can be overlooked by clinicians resulting in delayed diagnosis. This manuscript comments on Yang et al's article which reported 3 such cases. The main diagnostic features are based on routine morphology comprised of small cells with hyperchromatic nuclei, scant cytoplasm, brisk mitoses and necrosis. This can be supplemented by immunohistochemistry demonstrating positivity for cytokeratin, thyroid transcription factor-1 and neuroendocrine markers as well as a high Ki-67 labelling index. Imaging modalities such as positron emission tomography/contrast computed tomography help to confirm lung origin and rule out the possibility of extra-pulmonary small cell carcinoma. The predominant mechanism of spread is most likely hematogeneous. Prognosis is generally poor since this represents stage 4 disease but survival can be improved by chemo/radiotherapy and palliative surgery in select cases. Though outcomes have not changed much in the last several decades, the recent Food and Drug Administration approval of immune checkpoint inhibitors was a significant milestone as was the delineation of small cell lung carcinoma molecular subtypes. Liquid biopsies are increasingly being used for biomarker studies in clinical trials to assess treatment response and prognosis.
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Affiliation(s)
- Terence N Moyana
- Diagnostic and Molecular Pathology, The Ottawa Hospital and University of Ottawa, Ottawa K1H 8L6, Ontario, Canada
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27
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Lee YS, Kwon RJ, Lee HS, Chung JH, Kim YS, Jeong HS, Park SJ, Lee SY, Kim T, Yoon SH. The Role of Pentacyclic Triterpenoids in Non-Small Cell Lung Cancer: The Mechanisms of Action and Therapeutic Potential. Pharmaceutics 2024; 17:22. [PMID: 39861671 PMCID: PMC11768946 DOI: 10.3390/pharmaceutics17010022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 01/27/2025] Open
Abstract
Lung cancer remains a major global health problem because of its high cancer-related mortality rate despite advances in therapeutic approaches. Non-small cell lung cancer (NSCLC), a major subtype of lung cancer, is more amenable to surgical intervention in its early stages. However, the prognosis for advanced NSCLC remains poor, owing to limited treatment options. This underscores the growing need for novel therapeutic strategies to complement existing treatments and improve patient outcomes. In recent years, pentacyclic triterpenoids, a group of natural compounds, have emerged as promising candidates for cancer therapy due to their anticancer properties. Pentacyclic triterpenoids, such as lupeol, betulinic acid, betulin, oleanolic acid, ursolic acid, glycyrrhetinic acid, glycyrrhizin, and asiatic acid, have demonstrated the ability to inhibit cell proliferation and angiogenesis, induce apoptosis, suppress metastasis, and modulate inflammatory and immune pathways in NSCLC cell line models. These compounds exert their effects by modulating important signaling pathways such as NF-κB, PI3K/Akt, and MAPK. Furthermore, advances in drug delivery technologies such as nanocarriers and targeted delivery systems have improved the bioavailability and therapeutic efficacy of triterpenoids. However, despite promising preclinical data, rigorous clinical trials are needed to verify their safety and efficacy. This review explores the role of triterpenoids in NSCLC and therapeutic potential in preclinical models, focusing on their molecular mechanisms of action.
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Affiliation(s)
- Young-Shin Lee
- Family Medicine Clinic and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (Y.-S.L.); (R.J.K.); (H.S.L.)
| | - Ryuk Jun Kwon
- Family Medicine Clinic and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (Y.-S.L.); (R.J.K.); (H.S.L.)
| | - Hye Sun Lee
- Family Medicine Clinic and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea; (Y.-S.L.); (R.J.K.); (H.S.L.)
| | - Jae Heun Chung
- Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA;
| | - Yun Seong Kim
- Division of Pulmonology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea;
| | - Han-Sol Jeong
- School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.-S.J.); (S.-J.P.); (S.Y.L.)
| | - Su-Jung Park
- School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.-S.J.); (S.-J.P.); (S.Y.L.)
| | - Seung Yeon Lee
- School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.-S.J.); (S.-J.P.); (S.Y.L.)
| | - Taehwa Kim
- Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Pusan National University Hospital, Busan 49241, Republic of Korea;
| | - Seong Hoon Yoon
- Division of Pulmonology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea;
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28
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Wang B, Zhang J, Shi Y, Wang Y. Clinical significance of the combined systemic immune-inflammatory index and prognostic nutritional index in predicting the prognosis of patients with extensive-stage small-cell lung cancer receiving immune-combination chemotherapy. BMC Cancer 2024; 24:1574. [PMID: 39719567 DOI: 10.1186/s12885-024-13343-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 12/13/2024] [Indexed: 12/26/2024] Open
Abstract
BACKGROUND The therapeutic efficacy and prognosis of various tumors can be assessed using the systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI). Despite their potential, no studies have investigated the prognostic value of the combined SII-PNI score for outcomes in patients with extensive small cell lung cancer (ES-SCLC) treated with chemotherapy and immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS Our study retrospectively examined 213 ES-SCLC patients treated with chemotherapy and ICIs across two institutions. The patients were divided into three groups based on their SII-PNI scores. Cox regression analysis was employed to identify independent prognostic factors. A nomogram was constructed based on these independent factors. With 1000 repeated samples, the bootstrap method was used to validate the nomogram model internally. The model's performance was assessed using calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). RESULT Before and after chemotherapy with immune checkpoint inhibitors (ICIs), SII was significantly higher in the PD group compared with the PR group (both p < 0.05). In the meantime, PNI was considerably lower in the PD group than in the PR group (both p < 0.01). Kaplan-Meier curves demonstrated that patients with a low SII-PNI had prolonged progression-free survival (PFS) and overall survival (OS) compared to those with a high SII-PNI (all p < 0.01). Multivariate Cox analysis showed that PS = 1, bone metastasis, brain metastasis, and SII-PNI = 1,2 after four treatment cycles were independent risk factors for shorter OS and were included in the nomogram model. The ROC curves, C-index, and DCA curves confirm that the SII-PNI scores-based nomograms have strong predictive accuracy for OS. CONCLUSION There was a significant correlation between pre- and post-treatment SII-PNI and treatment effect in ES-SCLC. The SII-PNI score after four treatment cycles is a useful prognostic indicator for ES-SCLC patients receiving chemotherapy combined with immune checkpoint inhibitors (ICIs).
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Affiliation(s)
- Bingbing Wang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150000, China
| | - Jingdan Zhang
- Department of Gastroenterology, Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, 028000, China
| | - Yingnan Shi
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150000, China
| | - Yan Wang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150000, China.
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Sharma G, Abdullah KM, Qais FA, Khan P, Cox JL, Sarwar T, Nasser MW, Batra SK, Siddiqui JA. Clofazimine inhibits small-cell lung cancer progression by modulating the kynurenine/aryl hydrocarbon receptor axis. Int J Biol Macromol 2024; 282:136921. [PMID: 39490481 PMCID: PMC12060262 DOI: 10.1016/j.ijbiomac.2024.136921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/07/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024]
Abstract
Small cell lung cancer (SCLC) is one of the highly metastatic malignancies that contributes to ∼15 % of all lung cancers. Most SCLC patients (50-60 %) develop osteolytic bone metastases, significantly affecting their quality of life. Among several factors, environmental pollutant 2,3,7,8-Tetrachlorodibenzodioxin (TCDD) and kynurenine (Kyn), an endogenous ligand derived from tryptophan (Trp) metabolism, activate the aryl hydrocarbon receptor (AhR) and are responsible for SCLC progression and metastasis. Further, elevated AhR expression in bone cells intensifies bone resorption, making the Kyn/AhR axis a potential target for the bone metastatic propensity of SCLC. We first assessed the expression profile of AhR in human SCLC cell lines and found a significantly increased expression compared to normal lung cells. Additionally, we also evaluated the clinical significance of AhR expression in the patient samples of SCLC along with the relevance of the same in the Rb1fl/fl; Trp53fl/fl; MycLSL/LSL (RPM) mouse model using immunohistochemistry and found the higher AhR expression in the patient samples and RPM mouse tumor tissues. Using computational simulations, we found that clofazimine (CLF) binds at the activator (Kyn) binding site by forming a stable complex with AhR. The CLF binding with AhR was favored by Van der Waals and hydrophobic forces, and the proteins retained their secondary structure. Furthermore, we found that Kyn treatment potentiates the migration and clonogenic ability of SCLC cell lines by activating Erk/Akt oncogenic signaling. Treatment with CLF reduces AhR expression, which inhibits Kyn-mediated proliferation of SCLC cells, induces apoptosis, and cell cycle arrest in the G2/M phase. Further, our examination indicates that Kyn treatment also promotes osteoblast-mediated osteoclast differentiation through RANKL. The treatment with CLF impedes RANKL expression and osteoclastogenesis, suggesting that CLF has the potential to be used as the therapeutic for SCLC patients having bone metastasis.
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Affiliation(s)
- Gunjan Sharma
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson MS-39216, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA; Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson MS-39216, USA
| | - K M Abdullah
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson MS-39216, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA; Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson MS-39216, USA
| | - Faizan Abul Qais
- Department of Agricultural Microbiology, Faculty of Agricultural Sciences, Aligarh Muslim University, Aligarh, UP 202002, India
| | - Parvez Khan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA
| | - Jesse L Cox
- Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center, Omaha NE-68198, USA
| | - Tarique Sarwar
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
| | - Mohd Wasim Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Jawed A Siddiqui
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson MS-39216, USA; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA; Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson MS-39216, USA.
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Li X, Wu Y, Jin Y. Exosomal LncRNAs and CircRNAs in lung cancer: Emerging regulators and potential therapeutic targets. Noncoding RNA Res 2024; 9:1069-1079. [PMID: 39022675 PMCID: PMC11254510 DOI: 10.1016/j.ncrna.2024.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/11/2024] [Accepted: 06/11/2024] [Indexed: 07/20/2024] Open
Abstract
Lung cancer remains one of the most prevalent and lethal malignancies globally, characterized by high incidence and mortality rates among all cancers. The delayed diagnosis of lung cancer at intermediate to advanced stages frequently leads to suboptimal treatment outcomes. To improve the management of this disease, it is imperative to identify new, highly sensitive prognostic and diagnostic biomarkers. Exosomes, extracellular vesicles with a lipid-bilayer structure and a size range of 30-150 nm, are pivotal in intercellular communication and play significant roles in lung cancer progression. Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), are highly prevalent within exosomes and play a crucial role in various pathophysiological processes mediated by these extracellular vesicles. Beyond their established functions in miRNA and protein sequestration, these ncRNAs are involved in regulating translation and interactions within exosomes. Numerous studies have highlighted the importance of exosomal lncRNAs and circRNAs in influencing epithelial-mesenchymal transition (EMT), angiogenesis, proliferation, invasion, migration, and metastasis in lung cancer. Due to their unique functional characteristics, these molecules are promising therapeutic targets and biomarkers for diagnosis and prognosis. This review provides a succinct summary of the formation of exosomal lncRNAs and circRNAs, clarifies their biological roles, and thoroughly explains the mechanisms by which they participate in the progression of lung cancer. Finally, we discuss the potential clinical applications and challenges associated with exosomal lncRNAs and circRNAs in lung cancer.
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Affiliation(s)
- Xia Li
- Center of Molecular Diagnostic, Northern Jiangsu People's Hospital of Jiangsu Province, Yangzhou, 225001, China
| | - Yunbing Wu
- Department of Medicine Laboratory, Northern Jiangsu People's Hospital of Jiangsu Province, Yangzhou, 225001, China
| | - Yue Jin
- Center of Molecular Diagnostic, Northern Jiangsu People's Hospital of Jiangsu Province, Yangzhou, 225001, China
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31
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Fan L, Lin Y, Fu Y, Wang J. Small cell lung cancer with liver metastases: from underlying mechanisms to treatment strategies. Cancer Metastasis Rev 2024; 44:5. [PMID: 39585433 DOI: 10.1007/s10555-024-10220-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 11/06/2024] [Indexed: 11/26/2024]
Abstract
Small cell lung cancer (SCLC) represents an aggressive neuroendocrine (NE) tumor within the pulmonary region, characterized by very poor prognoses. Druggable targets for SCLC remain limited, thereby constraining treatment options available to patients. Immuno-chemotherapy has emerged as a pivotal therapeutic strategy for extensive-stage SCLC (ES-SCLC), yet it fails to confer significant efficacy in cases involving liver metastases (LMs) originating from SCLC. Therefore, our attention is directed towards the challenging subset of SCLC patients with LMs. Disease progression of LM-SCLC patients is affected by various factors in the tumor microenvironment (TME), including immune cells, blood vessels, inflammatory mediators, metabolites, and NE substances. Beyond standard immuno-chemotherapy, ongoing efforts to manage LMs in SCLC encompass anti-angiogenic therapy, radiotherapy, microwave ablation (MWA) / radiofrequency ablation (RFA), trans-arterial chemoembolization (TACE), and systemic therapies in conjunction with local interventions. Prospective experimental and clinical investigations into SCLC should prioritize precise and individualized approaches to enhance the prognosis across distinct patient cohorts.
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Affiliation(s)
- Linjie Fan
- CAMS Key Laboratory of Translational Research on Lung Cancer, State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yiwen Lin
- CAMS Key Laboratory of Translational Research on Lung Cancer, State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yunjie Fu
- School of Basic Medical Sciences, Peking University, Beijing, China
| | - Jie Wang
- CAMS Key Laboratory of Translational Research on Lung Cancer, State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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Chen C, Liu J, Zhang H, Zhang H, Liang Y, Ye Q, Shen W, Luo H, Guo L. A Bait-and-Hook Hydrogel for Net Tumor Cells to Enhance Chemotherapy and Mitigate Metastatic Dissemination. Pharmaceutics 2024; 16:1516. [PMID: 39771496 PMCID: PMC11728792 DOI: 10.3390/pharmaceutics16121516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/24/2024] [Accepted: 11/20/2024] [Indexed: 01/16/2025] Open
Abstract
Background: Lung cancer is an aggressive disease with rapid progression and a high rate of metastasis, leading to a significantly poor prognosis for many patients. While chemotherapy continues to serve as a cornerstone treatment for a large proportion of lung cancer patients, expanding preclinical and clinical evidence indicates that chemotherapy may promote tumor metastasis and cause side effects. Methods: We develop an injectable bait-and-hook hydrogel (BH-gel) for targeted tumor cell eradication, which embedded doxorubicin liposomes as cytotoxic agents and CXCL12 as a chemoattractant to capture and kill tumor cells. The hydrogel backbone was formed through covalent cross-linking between PVA and borax. In vitro, we investigated tumor recruitment and the antitumor effects in A549 cells. In vivo, we explored the anti-metastatic and antitumor activities against lung cancer. Results: BH-gel retained CXCL12 within its three-dimensional porous architecture for gradual release, effectively recruiting tumor cells. In contrast, blank hydrogel failed to achieve this. After encapsulation in BH-gel, the therapeutic efficacy of doxorubicin liposomes for tumor eradication was markedly improved, significantly reducing metastatic tumor presence to near-undetectable levels, while also resulting in notable reductions in cardiotoxicity and hepatotoxicity. Notably, BH-gel adhered well to tissues and exhibited exceptional electrical conductivity, which may be further developed into a real-time tumor monitoring system, facilitating timely therapeutic adjustments. Conclusions: BH-gel utilizes CXCL12 as a bait to recruit and entrap tumor cells in a three-dimensional porous matrix and subsequently kill them with embedded doxorubicin liposomes, thereby tackling the issue of metastatic spread. This bait-and-hook strategy has significant implications for the field of anti-metastasis medicine and shows considerable potential for clinical application.
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Affiliation(s)
- Cailian Chen
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; (C.C.); (J.L.); (H.Z.); (Q.Y.); (W.S.)
| | - Jinying Liu
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; (C.C.); (J.L.); (H.Z.); (Q.Y.); (W.S.)
| | - Hongbo Zhang
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China;
| | - Hongrui Zhang
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; (C.C.); (J.L.); (H.Z.); (Q.Y.); (W.S.)
| | - Yanhui Liang
- Institute of Drug Testing, Hainan Academy of Inspection and Testing, Haikou 570311, China;
| | - Qilian Ye
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; (C.C.); (J.L.); (H.Z.); (Q.Y.); (W.S.)
| | - Wei Shen
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; (C.C.); (J.L.); (H.Z.); (Q.Y.); (W.S.)
| | - Haibin Luo
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; (C.C.); (J.L.); (H.Z.); (Q.Y.); (W.S.)
| | - Ling Guo
- Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China; (C.C.); (J.L.); (H.Z.); (Q.Y.); (W.S.)
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Dursun CU, Tugcu AO, Dogru GD. Gastric metastasis of small cell lung carcinoma: A rare but noteworthy entity to consider. World J Clin Oncol 2024; 15:1379-1382. [DOI: 10.5306/wjco.v15.i10.1379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 09/29/2024] Open
Abstract
Small cell lung carcinoma (SCLC) is an aggressive malignancy known for its propensity for early and extensive metastatic spread. Gastric metastasis, where cancer cells disseminate from the lung to the stomach, is a rare but increasingly recognized complication of SCLC. This review provides a comprehensive overview of gastric metastasis in SCLC, addressing its clinical significance, diagnostic challenges, management strategies, and prognosis. Additionally, it examines the broader metastatic patterns of SCLC and compares them with other malignancies known for gastric metastasis. Gastric metastasis in SCLC, though infrequent, is clinically significant and often indicates advanced disease with a poor prognosis. SCLC typically metastasizes to the liver, brain, bones, and adrenal glands, with the stomach being an unusual site. The incidence of gastric metastasis ranges from 1% to 5% in autopsy studies, although this may be underestimated due to diagnostic difficulties and asymptomatic early lesions. Diagnosing gastric metastasis presents several challenges, including the asymptomatic nature of many cases, limitations of conventional imaging techniques, and difficulties in distinguishing metastatic lesions from primary gastric cancer via endoscopy. Histopathological diagnosis requires careful examination to identify SCLC cells through their characteristic small cell morphology and neuroendocrine markers. Management of gastric metastasis in SCLC typically involves a multidisciplinary approach. Systemic therapy, primarily chemotherapy, remains the cornerstone of treatment, with palliative care addressing symptoms and complications. Surgical intervention is usually reserved for specific cases requiring symptomatic relief. The prognosis for patients with gastric metastasis from SCLC is generally poor, reflecting the advanced stage of the disease. Median survival is significantly reduced compared to patients without gastric metastasis. This review emphasizes the need for enhanced awareness and early detection to improve patient outcomes and highlights the importance of ongoing research into better diagnostic and therapeutic strategies.
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Affiliation(s)
- Cemal Ugur Dursun
- Department of Radiation Oncology, Kartal Dr. Lutfi Kirdar City Hospital, İstanbul 34865, Türkiye
| | - Ahmet Oguz Tugcu
- Department of Radiation Oncology, Gulhane Training and Research Hospital, Ankara 06010, Türkiye
| | - Galip Dogukan Dogru
- Department of Radiation Oncology, Gulhane Training and Research Hospital, Ankara 06010, Türkiye
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Dowlati A, Hummel HD, Champiat S, Olmedo ME, Boyer M, He K, Steeghs N, Izumi H, Johnson ML, Yoshida T, Bouchaab H, Borghaei H, Felip E, Jost PJ, Gadgeel S, Chen X, Yu Y, Martinez P, Parkes A, Paz-Ares L. Sustained Clinical Benefit and Intracranial Activity of Tarlatamab in Previously Treated Small Cell Lung Cancer: DeLLphi-300 Trial Update. J Clin Oncol 2024; 42:3392-3399. [PMID: 39208379 PMCID: PMC11458107 DOI: 10.1200/jco.24.00553] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/30/2024] [Accepted: 07/22/2024] [Indexed: 09/04/2024] Open
Abstract
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3, has shown durable anticancer activity and manageable safety in previously treated small cell lung cancer (SCLC) in DeLLphi-300 phase I and DeLLphi-301 phase II trials. Here, we report extended follow-up of DeLLphi-300 (median follow-up, 12.1 months [range, 0.2-34.3]) in fully enrolled cohorts treated with tarlatamab ≥10 mg dose administered once every two weeks, once every three weeks, or once on day 1 and once on day 8 of a 21-day cycle (N = 152). Overall, the objective response rate (ORR) was 25.0%; the median duration of response (mDOR) was 11.2 months (95% CI, 6.6 to 22.3), and the median overall survival (mOS) was 17.5 months (95% CI, 11.4 to not estimable [NE]). Among 17 patients receiving 10 mg tarlatamab once every two weeks, the ORR was 35.3%, the mDOR was 14.9 months (95% CI, 3.0 to NE), the mOS was 20.3 months (95% CI, 5.1 to NE), and 29.4% had sustained disease control with time on treatment ≥52 weeks. No new safety signals were identified. In modified Response Assessment in Neuro-Oncology Brain Metastases analyses, CNS tumor shrinkage of ≥30% was observed in 62.5% of patients (10 of 16) who had a baseline CNS lesion of ≥10 mm, including in a subset of patients with tumor shrinkage long after previous brain radiotherapy. In DeLLphi-300 extended follow-up, tarlatamab demonstrated unprecedented survival and potential findings of intracranial activity in previously treated SCLC.
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Affiliation(s)
- Afshin Dowlati
- University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH
| | - Horst-Dieter Hummel
- Translational Oncology/Early Clinical Trial Unit (ECTU), Bavarian Cancer Research Center, National Center for Tumor Diseases, Comprehensive Cancer Center Mainfranken and University Hospital Würzburg, Würzburg, Germany
| | - Stephane Champiat
- Department of Therapeutic Innovation and Early Phase Trials, Gustave Roussy, Villejuif, France
| | - Maria Eugenia Olmedo
- Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid, Spain
| | - Michael Boyer
- Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia
- Faculty of Medicine and Health, School of Medicine, University of Sydney, Sydney, Australia
| | - Kai He
- Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH
| | - Neeltje Steeghs
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Hiroki Izumi
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Melissa L. Johnson
- Department of Medical Oncology, Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN
| | - Tatsuya Yoshida
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hasna Bouchaab
- Department of Oncology, Vaud University Hospital, Lausanne, Switzerland
| | | | - Enriqueta Felip
- Department of Medical Oncology, Hospital Universitario del Vall d'Hebron, Barcelona, Spain
| | - Philipp J. Jost
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Shirish Gadgeel
- Division of Hematology and Oncology, Department of Internal Medicine, Henry Ford Cancer Institute/Henry Ford Health System, Detroit, MI
| | - Xi Chen
- Amgen Inc, Thousand Oaks, CA
| | | | | | | | - Luis Paz-Ares
- Hospital Universitario 12 de Octubre, CNIO-H12o Lung Cancer Unit, Complutense University and Ciberonc, Madrid, Spain
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He C. Activating Invasion and Metastasis in Small Cell Lung Cancer: Role of the Tumour Immune Microenvironment and Mechanisms of Vasculogenesis, Epithelial-Mesenchymal Transition, Cell Migration, and Organ Tropism. Cancer Rep (Hoboken) 2024; 7:e70018. [PMID: 39376011 PMCID: PMC11458887 DOI: 10.1002/cnr2.70018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 08/06/2024] [Accepted: 09/09/2024] [Indexed: 10/09/2024] Open
Abstract
BACKGROUND Small cell lung cancer (SCLC) harbours the most aggressive phenotype of all lung cancers to correlate with its bleak prognosis. The aggression of SCLC is partially attributable to its strong metastatic tendencies. The biological processes facilitating the metastasis in SCLC are still poorly understood and garnering a deeper understanding of these processes may enable the exploration of additional targets against this cancer hallmark in the treatment of SCLC. RECENT FINDINGS This narrative review will discuss the proposed molecular mechanisms by which the cancer hallmark of activating invasion and metastasis is featured in SCLC through important steps of the metastatic pathway, and address the various molecular targets that may be considered for therapeutic intervention. The tumour immune microenvironment plays an important role in facilitating immunotherapy resistance, whilst the poor infiltration of natural killer cells in particular fosters a pro-metastatic environment in SCLC. SCLC vasculogenesis is achieved through VEGF expression and vascular mimicry, and epithelial-mesenchymal transition is facilitated by the expression of the transcriptional repressors of E-cadherin, the suppression of the Notch signalling pathway and tumour heterogeneity. Nuclear factor I/B, selectin and B1 integrin hold important roles in SCLC migration, whilst various molecular markers are expressed by SCLC to assist organ-specific homing during metastasis. The review will also discuss a recent article observing miR-1 mRNA upregulation as a potential therapeutic option in targeting the metastatic activity of SCLC. CONCLUSION Treatment of SCLC remains a clinical challenge due to its recalcitrant and aggressive nature. Amongst the many hallmarks used by SCLC to enable its aggressive behaviour, that of its ability to invade surrounding tissue and metastasise is particularly notable and understanding the molecular mechanisms in SCLC metastasis can identify therapeutic targets to attenuate SCLC aggression and improve mortality.
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Affiliation(s)
- Carl He
- Department of Oncology, Eastern HealthUniversity of MelbourneMelbourneAustralia
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Li GS, Huang ZG, He RQ, Zhang W, Tang YX, Liu ZS, Gan XY, Tang D, Li DM, Tang YL, Zhan YT, Dang YW, Zhou HF, Zheng JH, Jin MH, Tian J, Chen G. ITGB4 Serves as an Identification and Prognosis Marker Associated with Immune Infiltration in Small Cell Lung Carcinoma. Mol Biotechnol 2024; 66:2956-2971. [PMID: 37847361 DOI: 10.1007/s12033-023-00912-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 09/15/2023] [Indexed: 10/18/2023]
Abstract
Integrin beta 4 (ITGB4) is a vital factor for numerous cancers. However, no reports regarding ITGB4 in small cell lung carcinoma (SCLC) have been found in the existing literature. This study systematically investigated the expression and clinical value of ITGB4 in SCLC using multi-center and large-sample (n = 963) data. The ITGB4 expression levels between SCLC and control tissues were compared using standardized mean difference and Wilcoxon rank-sum test. The clinical significance of the gene in SCLC was observed using Cox regression and Kaplan-Meier curves. ITGB4 is overexpressed in multiple cancers and represents significant value in distinguishing among cancer samples (AUC = 0.91) and predicting the prognoses (p < 0.05) of patients with different cancers. In contrast, decreased ITGB4 mRNA expression was determined in SCLC (SMD < 0), and this finding was further confirmed at protein levels using in-house specimens (p < 0.05). This decrease in expression may be attributed to the regulatory role of estrogen receptor 1. ITGB4 may participate in the progression of SCLC by affecting several signaling pathways (e.g., tumor necrosis factor signaling pathway) and a series of immune cells (e.g., dendritic cells) (p < 0.05). The gene may serve as a potential marker for predicting the disease status (AUC = 0.97) and prognoses (p < 0.05) of patients with SCLC. Collectively, ITGB4 was identified as an identification and prognosis marker associated with immune infiltration in SCLC.
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Affiliation(s)
- Guo-Sheng Li
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Zhi-Guang Huang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Rong-Quan He
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Wei Zhang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Yu-Xing Tang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Zhi-Su Liu
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Xiang-Yu Gan
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Deng Tang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Dong-Ming Li
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Yu-Lu Tang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Yan-Ting Zhan
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Yi-Wu Dang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Hua-Fu Zhou
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Jin-Hua Zheng
- Department of Pathology, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, People's Republic of China
| | - Mei-Hua Jin
- Department of Pathology, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, People's Republic of China
| | - Jia Tian
- Department of Pathology, The Affiliated Hospital of Guilin Medical University, Guilin, 541001, People's Republic of China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China.
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Wen Y, Sun X, Zeng L, Liang S, Li D, Chen X, Zeng F, Zhang C, Wang Q, Zhong Q, Deng L, Guo L. CDK4/6 Inhibitors Impede Chemoresistance and Inhibit Tumor Growth of Small Cell Lung Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2400666. [PMID: 39136283 PMCID: PMC11481398 DOI: 10.1002/advs.202400666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 06/21/2024] [Indexed: 10/17/2024]
Abstract
Small cell lung cancer (SCLC) is characterized by rapid development of chemoresistance and poor outcomes. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are widely used in breast cancer and other cancer types. However, the molecular mechanisms of CDK4/6 in SCLC chemoresistance remain poorly understood. Here, Rb1flox/flox, Trp53flox/flox, Ptenflox/flox (RTP) and Rb1flox/flox, Trp53flox/flox, MycLSL/LSL (RPM) spontaneous SCLC mouse models, SCLC cell line-derived xenograft (CDX) models, and SCLC patient-derived xenograft (PDX) models are established to reveal the potential effects of CDK4/6is on SCLC chemoresistance. In this study, it is found that CDK4/6is palbociclib (PD) or ribociclib (LEE) combined with chemotherapeutic drugs significantly inhibit SCLC tumor growth. Mechanistically, CDK4/6is do not function through the classic Retionblastoma1 (RB) dependent axis in SCLC. CDK4/6is induce impair autophagy through the AMBRA1-lysosome signaling pathway. The upregulated AMBRA1 protein expression leads to CDK6 degradation via autophagy, and the following TFEB and TFE3 nuclear translocation inhibition leading to the lysosome-related genes levels downregulation. Moreover, it is found that the expression of CDK6 is higher in SCLC tumors than in normal tissue and it is associated with the survival and prognosis of SCLC patients. Finally, these findings demonstrate that combining CDK4/6is with chemotherapy treatment may serve as a potential therapeutic option for SCLC patients.
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Affiliation(s)
- Yang Wen
- Department of PathologyZhujiang HospitalSouthern Medical UniversityGuangzhou510080China
| | - Xue Sun
- Department of PathologyZhujiang HospitalSouthern Medical UniversityGuangzhou510080China
| | - Lingge Zeng
- Department of PathologyZhujiang HospitalSouthern Medical UniversityGuangzhou510080China
| | - Shumei Liang
- Department of PathologyGuangzhou First People's HospitalSchool of MedicineSouth China University of TechnologyGuangzhou510180China
- Department of PathologyGuangzhou First People's HospitalGuangzhou Medical UniversityGuangzhou510180China
| | - Deyu Li
- Department of OncologyFujian Provincial HospitalFuzhou350001China
| | - Xiangtian Chen
- Department of PathologyZhujiang HospitalSouthern Medical UniversityGuangzhou510080China
| | - Fanrui Zeng
- Department of Radiation OncologyThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou510120China
| | - Chao Zhang
- Department of OncologyZhujiang HospitalSouthern Medical UniversityGuangzhou510080China
| | - Qiongyao Wang
- Department of OncologyZhujiang HospitalSouthern Medical UniversityGuangzhou510080China
| | - Qinsong Zhong
- Department of PathologyZhujiang HospitalSouthern Medical UniversityGuangzhou510080China
| | - Ling Deng
- Department of PathologyZhujiang HospitalSouthern Medical UniversityGuangzhou510080China
| | - Linlang Guo
- Department of PathologyZhujiang HospitalSouthern Medical UniversityGuangzhou510080China
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Zhang C, Chen J, Wu H, Wang J, Gao L, Zhao J, Sun Y, Jia Z, Mu X, Bai C, Wang R, Wu K, Liu Q, Shi Y. Efficacy and safety of anlotinib plus penpulimab as second-line treatment for small cell lung cancer: A multicenter, open-label, single-arm phase II trial. CANCER PATHOGENESIS AND THERAPY 2024; 2:268-275. [PMID: 39371104 PMCID: PMC11447333 DOI: 10.1016/j.cpt.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 02/01/2024] [Accepted: 02/04/2024] [Indexed: 10/08/2024]
Abstract
BACKGROUND Currently, the need for new therapeutic strategies involving programmed cell death protein-1 (PD-1) monoclonal antibodies in the second-line setting of small cell lung cancer (SCLC) is urgent. This study aimed to evaluate the efficacy and safety of anlotinib plus penpulimab as a second-line treatment for patients with SCLC who progressed after first-line platinum-based chemotherapy. METHODS This study included the patients from Cohort 4 of a single-arm, open-label, multicenter, phase II clinical trial. A safety run-in phase was performed under anlotinib (10/12 mg quaque die [QD], days 1-14) plus penpulimab (200 mg intravenously [IV], day 1) in a 21-day cycle, followed by the formal trial in which the patients received anlotinib (12 mg QD, days 1-14) plus penpulimab (200 mg IV, day 1) in a 21-day cycle. The primary endpoint of the safety run-in phase was safety. The primary endpoint of the formal trial phase was the objective response rate (ORR). RESULTS From April 28, 2020, to November 24, 2020, 21 patients were enrolled from 11 hospitals, including 2 in the safety run-in phase and 19 in the formal trial phase. In the formal trial phase, the ORR was 42.1% (8/19; 95% confidence interval [CI]: 17.7-66.6%). The median progression-free survival was 4.8 months (95% CI: 2.9-11.3 months), and the median overall survival was 13.0 months (95% CI: 4.6-not applicable [NA] months). The incidence of ≥grade 3 treatment-related adverse events (TRAEs) was 52.4% (11/21), and the incidence of treatment-related serious adverse events (AEs) was 28.6% (6/21). Two AE-related deaths occurred. The most common AEs were hypertension (57.1%, 12/21), hypothyroidism (42.9%, 9/21), and hypertriglyceridemia (38.1%, 8/21). CONCLUSIONS In patients with SCLC who progressed after first-line platinum-based chemotherapy, the second-line anlotinib plus penpulimab treatment demonstrates promising anti-cancer activity and a manageable safety profile, which warrants further investigation. TRIAL REGISTRATION No. NCT04203719, https://clinicaltrials.gov/.
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Affiliation(s)
- Changgong Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing 100021, China
| | - Jianhua Chen
- Department I of Thoracic Oncology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410083, China
| | - Huijuan Wu
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China
| | - Jun Wang
- Department II of Head and Neck Tumor, Gansu Provincial Cancer Hospital, Lanzhou, Gansu 730050, China
| | - Liying Gao
- Department III of Radiotherapy, Gansu Provincial Cancer Hospital, Lanzhou, Gansu 730050, China
| | - Jun Zhao
- Department I of Thoracic Oncology, Beijing Cancer Hospital, Beijing 100142, China
| | - Yan Sun
- Department I of Thoracic Oncology, Beijing Cancer Hospital, Beijing 100142, China
| | - Zhongyao Jia
- Department of Oncology, Linyi People's Hospital, Linyi, Shandong 276002, China
| | - Xinlin Mu
- Department of Respiratory and Critical Care Medicine, Peking University People's Hospital, Beijing 100032, China
| | - Chunmei Bai
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Rui Wang
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China
| | - Kailiang Wu
- Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai 200030, China
| | - Qiang Liu
- Department I of Oncology, Shenyang Chest Hospital, Shenyang, Liaoning 110044, China
| | - Yuankai Shi
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing 100021, China
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Hartmann GG, Sage J. Small Cell Lung Cancer Neuronal Features and Their Implications for Tumor Progression, Metastasis, and Therapy. Mol Cancer Res 2024; 22:787-795. [PMID: 38912893 PMCID: PMC11374474 DOI: 10.1158/1541-7786.mcr-24-0265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/30/2024] [Accepted: 06/20/2024] [Indexed: 06/25/2024]
Abstract
Small cell lung cancer (SCLC) is an epithelial neuroendocrine form of lung cancer for which survival rates remain dismal and new therapeutic approaches are greatly needed. Key biological features of SCLC tumors include fast growth and widespread metastasis, as well as rapid resistance to treatment. Similar to pulmonary neuroendocrine cells, SCLC cells have traits of both hormone-producing cells and neurons. In this study, we specifically discuss the neuronal features of SCLC. We consider how neuronal G protein-coupled receptors and other neuronal molecules on the surface of SCLC cells can contribute to the growth of SCLC tumors and serve as therapeutic targets in SCLC. We also review recent evidence for the role of neuronal programs expressed by SCLC cells in the fast proliferation, migration, and metastasis of these cells. We further highlight how these neuronal programs may be particularly relevant for the development of brain metastases and how they can assist SCLC cells to functionally interact with neurons and astrocytes. A greater understanding of the molecular and cellular neuronal features of SCLC is likely to uncover new vulnerabilities in SCLC cells, which may help develop novel therapeutic approaches. More generally, the epithelial-to-neuronal transition observed during tumor progression in SCLC and other cancer types can contribute significantly to tumor development and response to therapy.
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Affiliation(s)
- Griffin G. Hartmann
- Departments of Pediatrics and Genetics, Stanford University, Stanford, CA, USA
| | - Julien Sage
- Departments of Pediatrics and Genetics, Stanford University, Stanford, CA, USA
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Yin H, Hu Z, Yang J. Risk factors and nomograms for diagnosis and early death in patients with combined small cell lung cancer with distant metastasis: a population-based study. J Int Med Res 2024; 52:3000605241238689. [PMID: 39291412 PMCID: PMC11418558 DOI: 10.1177/03000605241238689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 02/21/2024] [Indexed: 09/19/2024] Open
Abstract
OBJECTIVE Combined small cell lung cancer (CSCLC) with distant metastasis (DM) is an aggressive disease with a poor prognosis. Effective nomograms are needed to predict DM and early death in patients with CSCLC and DM. METHODS This retrospective study included patients with CSCLC from the Surveillance, Epidemiology, and End Results database between 2004 and 2015. Risk factors for DM and early death were analyzed by univariate and multivariate logistic regression. Nomograms were constructed based on the results in a training cohort and confirmed in a validation cohort, and their performances were assessed by concordance index (C-index), receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA). RESULTS A total of 788 patients with CSCLC were selected, including 364 patients with metastatic CSCLC. Sex, tumor site, T stage, and N stage were independent risk factors for DM, while age, surgery, chemotherapy, and liver metastasis were independent risk factors for early death. C-index, ROC, calibration, and DCA curve analyses all showed good predictive performances for both nomograms. CONCLUSIONS These nomograms could reliably predict DM risk in CSCLC patients and early death in CSCLC patients with DM, and may thus help clinicians to assess these risks and implement individualized therapies.
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Affiliation(s)
- Hui Yin
- Department of Biochemistry and Molecular Biology, Basic Medical College, Qingdao University, Qingdao, China
- Department of Thoracic Surgery, The First Affiliated Hospital Shaoyang University, Shaoyang, China
| | - Zhi Hu
- Department of Thoracic Surgery, The First Affiliated Hospital Shaoyang University, Shaoyang, China
| | - Jie Yang
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Wang H, Sun H, Huang J, Zhang Z, Cai G, Wang C, Xiao K, Xiong X, Zhang J, Liu P, Lu X, Feng W, Wang J. Therapeutic targeting ERRγ suppresses metastasis via extracellular matrix remodeling in small cell lung cancer. EMBO Mol Med 2024; 16:2043-2059. [PMID: 39085398 PMCID: PMC11393344 DOI: 10.1038/s44321-024-00108-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 06/30/2024] [Accepted: 07/09/2024] [Indexed: 08/02/2024] Open
Abstract
Small-cell lung cancer (SCLC) is the most aggressive and lethal type of lung cancer, characterized by limited treatment options, early and frequent metastasis. However, the determinants of metastasis in SCLC are poorly defined. Here, we show that estrogen-related receptor gamma (ERRγ) is overexpressed in metastatic SCLC tumors, and is positively associated with SCLC progression. ERRγ functions as an essential activator of extracellular matrix (ECM) remodeling and cell adhesion, two critical steps in metastasis, by directly regulating the expression of major genes involved in these processes. Genetic and pharmacological inhibition of ERRγ markedly reduces collagen production, cell-matrix adhesion, microfilament production, and eventually blocks SCLC cell invasion and tumor metastasis. Notably, ERRγ antagonists significantly suppressed tumor growth and metastasis and restored SCLC vulnerability to chemotherapy in multiple cell-derived and patient-derived xenograft models. Taken together, these findings establish ERRγ as an attractive target for metastatic SCLC and provide a potential pharmacological strategy for treating this lethal disease.
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Affiliation(s)
- Hong Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, 510006, Guangzhou, Guangdong, China
| | - Huizi Sun
- School of Pharmaceutical Sciences, Sun Yat-sen University, 510006, Guangzhou, Guangdong, China
| | - Jie Huang
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080, Guangzhou, China
| | - Zhenhua Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, 510006, Guangzhou, Guangdong, China
| | - Guodi Cai
- School of Pharmaceutical Sciences, Sun Yat-sen University, 510006, Guangzhou, Guangdong, China
| | - Chaofan Wang
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, 510632, Guangzhou, China
| | - Kai Xiao
- Precision Medicine Research Center, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, China
| | - Xiaofeng Xiong
- School of Pharmaceutical Sciences, Sun Yat-sen University, 510006, Guangzhou, Guangdong, China
| | - Jian Zhang
- Thoracic Surgery Department, The Third Affiliated Hospital of Sun Yat-sen University, No. 600, Tianhe Road, Tianhe District, 510630, Guangzhou, China
| | - Peiqing Liu
- School of Pharmaceutical Sciences, Sun Yat-sen University, 510006, Guangzhou, Guangdong, China
- National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-sen University, 510006, Guangzhou, Guangdong, PR China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, 510006, Guangzhou, Guangdong, P.R. China
| | - Xiaoyun Lu
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, 510632, Guangzhou, China.
| | - Weineng Feng
- Department of Pulmonary Oncology, The First People's Hospital of Foshan, 528000, Foshan, Guangdong, China.
| | - Junjian Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, 510006, Guangzhou, Guangdong, China.
- National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-sen University, 510006, Guangzhou, Guangdong, PR China.
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, 510006, Guangzhou, Guangdong, P.R. China.
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Mu X, Yu C, Zhao Y, Hu X, Wang H, He Y, Wu H. Exosomal miR-1228-5p down-regulates DUSP22 to promotes cell proliferation and migration in small cell lung cancer. Life Sci 2024; 351:122787. [PMID: 38851418 DOI: 10.1016/j.lfs.2024.122787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/29/2024] [Accepted: 06/04/2024] [Indexed: 06/10/2024]
Abstract
BACKGROUND Exosomes play a crucial role in promoting tumor progression, dissemination, and resistance to treatment. These extracellular vesicles hold promise as valuable indicators for cancer detection. Our investigation focuses on exploring the significance and clinical relevance of exosomal miRNAs in small cell lung cancer (SCLC). METHODS Serum exosomes were isolated from both SCLC patients and healthy controls, and subjected to exosomal miRNA sequencing analysis. Mimics and inhibitors were employed to investigate the function of exosomal miR-1128-5p in cell migration and proliferation, both in vitro and in vivo. Western blot and luciferase assay were utilized to identify the interaction between miR-1228-5p and dual specificity phosphatase 22 (DUSP22). RESULTS Exosomal miRNA sequencing analysis revealed enrichment of specific miRNAs in SCLC compared to healthy controls. Circulating miR-1228-5p was upregulated in SCLC patients, associated with advanced stages, suggesting its potential oncogenic role. In vitro, miR-1228-5p expression was significantly higher in SCLC cells than in normal cells. SCLC cell-derived exosomes contained elevated levels of miR-1228-5p, facilitating its entry into co-cultured cells. Notably, migration and proliferation induced by SCLC exosomes were mainly mediated by miR-1228-5p. In vivo experiments confirmed these findings. Western blot analysis demonstrated miR-1228-5p's regulation of DUSP22 expression, and luciferase reporter assay validated DUSP22 as a direct target gene. Overexpressing DUSP22 counteracted miR-1228-5p's promotion of SCLC cell proliferation and migration. CONCLUSIONS Collectively, our results suggest that exosomes play a role in facilitating cancer growth and metastasis by delivering miR-1228-5p. Moreover, circulating exosomal miR-1228-5p may serve as a potential marker for SCLC diagnosis and prognosis.
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Affiliation(s)
- Xiaoqian Mu
- Department of Interventional Pulmonology, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Chaonan Yu
- Department of Interventional Pulmonology, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Yanqiu Zhao
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Xiufeng Hu
- Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - He Wang
- Department of Interventional Pulmonology, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Yongqiang He
- Department of Respiratory Medicine, Hami Second People's, Hospital Hami Cancer Hospital, Hami, China
| | - Hongbo Wu
- Department of Interventional Pulmonology, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
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Zhang J, Liu X, Hou P, Lv Y, Li G, Cao G, Wang H, Lin W. BRCA1 orchestrates the response to BI-2536 and its combination with alisertib in MYC-driven small cell lung cancer. Cell Death Dis 2024; 15:551. [PMID: 39085197 PMCID: PMC11291995 DOI: 10.1038/s41419-024-06950-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 08/02/2024]
Abstract
PLK1 is currently at the forefront of mitotic research and has emerged as a potential target for small cell lung cancer (SCLC) therapy. However, the factors influencing the efficacy of PLK1 inhibitors remain unclear. Herein, BRCA1 was identified as a key factor affecting the response of SCLC cells to BI-2536. Targeting AURKA with alisertib, at a non-toxic concentration, reduced the BI-2536-induced accumulation of BRCA1 and RAD51, leading to DNA repair defects and mitotic cell death in SCLC cells. In vivo experiments confirmed that combining BI-2536 with alisertib impaired DNA repair capacity and significantly delayed tumor growth. Additionally, GSEA analysis and loss- and gain-of-function assays demonstrated that MYC/MYCN signaling is crucial for determining the sensitivity of SCLC cells to BI-2536 and its combination with alisertib. The study further revealed a positive correlation between RAD51 expression and PLK1/AURKA expression, and a negative correlation with the IC50 values of BI-2536. Manipulating RAD51 expression significantly influenced the efficacy of BI-2536 and restored the MYC/MYCN-induced enhancement of BI-2536 sensitivity in SCLC cells. Our findings indicate that the BRCA1 and MYC/MYCN-RAD51 axes govern the response of small cell lung cancer to BI-2536 and its combination with alisertib. This study propose the combined use of BI-2536 and alisertib as a novel therapeutic strategy for the treatment of SCLC patients with MYC/MYCN activation.
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Affiliation(s)
- Jiahui Zhang
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, Anhui, P.R. China
- University of Science and Technology of China, Hefei, 230026, Anhui, P.R. China
- The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, P.R. China
| | - Xiaoli Liu
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, Anhui, P.R. China
| | - Peng Hou
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, Anhui, P.R. China
- University of Science and Technology of China, Hefei, 230026, Anhui, P.R. China
- The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, P.R. China
| | - Yang Lv
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, Anhui, P.R. China
| | - Gongfeng Li
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, Anhui, P.R. China
- University of Science and Technology of China, Hefei, 230026, Anhui, P.R. China
- The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, P.R. China
| | - Guozhen Cao
- The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, P.R. China
| | - Huogang Wang
- High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, Anhui, P.R. China
| | - Wenchu Lin
- The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, P.R. China.
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Lara-Sáez I, Mencía Á, Recuero E, Li Y, García M, Oteo M, Gallego MI, Enguita AB, de Prado-Verdún D, A S, Wang W, García-Escudero R, Murillas R, Santos M. Nonviral CRISPR/Cas9 mutagenesis for streamlined generation of mouse lung cancer models. Proc Natl Acad Sci U S A 2024; 121:e2322917121. [PMID: 38959035 PMCID: PMC11252735 DOI: 10.1073/pnas.2322917121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 06/14/2024] [Indexed: 07/04/2024] Open
Abstract
Functional analysis in mouse models is necessary to establish the involvement of a set of genetic variations in tumor development. A modeling platform to facilitate and cost-effectively analyze the role of multiple genes in carcinogenesis would be valuable. Here, we present an innovative strategy for lung mutagenesis using CRISPR/Cas9 ribonucleoproteins delivered via cationic polymers. This approach allows the simultaneous inactivation of multiple genes. We validate the effectiveness of this system by targeting a group of tumor suppressor genes, specifically Rb1, Rbl1, Pten, and Trp53, which were chosen for their potential to cause lung tumors, namely small cell lung carcinoma (SCLC). Tumors with histologic and transcriptomic features of human SCLC emerged after intratracheal administration of CRISPR/polymer nanoparticles. These tumors carried loss-of-function mutations in all four tumor suppressor genes at the targeted positions. These findings were reproduced in two different pure genetic backgrounds. We provide a proof of principle for simplified modeling of lung tumorigenesis to facilitate functional testing of potential cancer-related genes.
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Affiliation(s)
- Irene Lara-Sáez
- Charles Institute of Dermatology, School of Medicine, University College Dublin, Belfield, DublinD04 V1W8, Ireland
| | - Ángeles Mencía
- Biomedical Innovation Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid28040, Spain
- CB06/07/0019 Unit, Centro de Investigación Biomédica en Red en Enfermedades Raras, Madrid28029, Spain
- Regenerative Medicine and Tissue Bioengineering Group, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid28040, Spain
| | - Enrique Recuero
- Biomedical Innovation Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid28040, Spain
- Cellular and Molecular Genitourinary Oncology Group, Institute of Biomedical Research Hospital “12 de Octubre”, Madrid28041, Spain
| | - Yinghao Li
- Charles Institute of Dermatology, School of Medicine, University College Dublin, Belfield, DublinD04 V1W8, Ireland
| | - Marta García
- CB06/07/0019 Unit, Centro de Investigación Biomédica en Red en Enfermedades Raras, Madrid28029, Spain
- Regenerative Medicine and Tissue Bioengineering Group, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid28040, Spain
- Department of Biomedical Engineering, Polytechnic School, Carlos III University, Leganés, Madrid28911, Spain
| | - Marta Oteo
- Biomedical Applications and Pharmacokinetics Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid28040, Spain
| | - Marta I. Gallego
- Unidad de Histología, Unidades Centrales Científico Tecnológicas, Instituto de Salud Carlos III, Madrid28220, Spain
| | - Ana Belén Enguita
- Pathology Department, University Hospital “12 de Octubre”, Madrid28041, Spain
| | - Diana de Prado-Verdún
- Biomedical Innovation Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid28040, Spain
- CB06/07/0019 Unit, Centro de Investigación Biomédica en Red en Enfermedades Raras, Madrid28029, Spain
- Regenerative Medicine and Tissue Bioengineering Group, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid28040, Spain
| | - Sigen A
- Research and Clinical Translation Center of Gene Medicine and Tissue Engineering, School of Public Health, Anhui University of Science and Technology, Huainan232001, China
| | - Wenxin Wang
- Charles Institute of Dermatology, School of Medicine, University College Dublin, Belfield, DublinD04 V1W8, Ireland
| | - Ramón García-Escudero
- Biomedical Innovation Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid28040, Spain
- Cellular and Molecular Genitourinary Oncology Group, Institute of Biomedical Research Hospital “12 de Octubre”, Madrid28041, Spain
- Tumor Progression Mechanisms Program, Centro de Investigación Biomédica en Red de Cáncer, Madrid28029, Spain
| | - Rodolfo Murillas
- Biomedical Innovation Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid28040, Spain
- CB06/07/0019 Unit, Centro de Investigación Biomédica en Red en Enfermedades Raras, Madrid28029, Spain
- Regenerative Medicine and Tissue Bioengineering Group, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid28040, Spain
| | - Mirentxu Santos
- Biomedical Innovation Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid28040, Spain
- Cellular and Molecular Genitourinary Oncology Group, Institute of Biomedical Research Hospital “12 de Octubre”, Madrid28041, Spain
- Tumor Progression Mechanisms Program, Centro de Investigación Biomédica en Red de Cáncer, Madrid28029, Spain
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Zhang J, Ma Y. Luteolin as a potential therapeutic candidate for lung cancer: Emerging preclinical evidence. Biomed Pharmacother 2024; 176:116909. [PMID: 38852513 DOI: 10.1016/j.biopha.2024.116909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 06/04/2024] [Accepted: 06/06/2024] [Indexed: 06/11/2024] Open
Abstract
Lung cancer is a prevalent malignant tumor and a leading cause of cancer-related fatalities globally. However, current treatments all have limitations. Therefore, there is an urgent need to identify a readily available therapeutic agent to counteract lung cancer development and progression. Luteolin is a flavonoid derived from vegetables and herbs that possesses preventive and therapeutic effects on various cancers. With the goal of providing new directions for the treatment of lung cancer, we review here the recent findings on luteolin so as to provide new ideas for the development of new anti-lung cancer drugs. The search focused on studies published between January 1995 and January 2024 that explored the use of luteolin in lung cancer. A comprehensive literature search was conducted in the SCOPUS, Google Scholar, PubMed, and Web of Science databases using the keywords "luteolin" and "lung cancer." By collecting previous literature, we found that luteolin has multiple mechanisms of therapeutic effects, including promotion of apoptosis in lung cancer cells; inhibition of tumor cell proliferation, invasion and metastasis; and modulation of immune responses. In addition, it can be used as an adjuvant to radio-chemotherapy and helps to ameliorate cancer complications. This review summarizes the structure, natural sources, physicochemical properties and pharmacokinetics of luteolin, and focuses on the anti-lung cancer mechanism of luteolin, so as to provide new ideas for the development of new anti-lung cancer drugs.
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Affiliation(s)
- Jin Zhang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, Liaoning 110004, PR China
| | - Yue Ma
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, Liaoning 110004, PR China.
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Dhingra S, Goyal S, Thirumal D, Sharma P, Kaur G, Mittal N. Mesoporous silica nanoparticles: a versatile carrier platform in lung cancer management. Nanomedicine (Lond) 2024; 19:1331-1346. [PMID: 39105754 PMCID: PMC11318747 DOI: 10.1080/17435889.2024.2348438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 04/24/2024] [Indexed: 08/07/2024] Open
Abstract
Mesoporous silica nanoparticles (MSNPs) are inorganic nanoparticles that have been comprehensively investigated and are intended to deliver therapeutic agents. MSNPs have revolutionized the therapy for various conditions, especially cancer and infectious diseases. In this article, the viability of MSNPs' administration for lung cancer therapy has been reviewed. However, certain challenges lay ahead in the successful translation such as toxicology, immunology, large-scale production, and regulatory matters have made it extremely difficult to translate such discoveries from the bench to the bedside. This review highlights recent developments, characteristics, mechanism of action and customization for targeted delivery. This review also covers the most recent data that sheds light on MSNPs' extraordinary therapeutic potential in fighting lung cancer as well as future hurdles.
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Affiliation(s)
- Smriti Dhingra
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Shuchi Goyal
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Divya Thirumal
- Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104,India
| | - Preety Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
| | - Gurpreet Kaur
- Department of Pharmaceutical Sciences & Drug Research, Punjabi University, Patiala, Punjab, 147002, India
| | - Neeraj Mittal
- Chitkara College of Pharmacy, Chitkara University, Punjab, 140401, India
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Zhou Y, Song L, Lyu L, Li S, Wang Q. Gastrointestinal stromal tumor with small cell carcinoma infiltration: a case report. Front Oncol 2024; 14:1389975. [PMID: 38952545 PMCID: PMC11215004 DOI: 10.3389/fonc.2024.1389975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 05/24/2024] [Indexed: 07/03/2024] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive system. They usually occur in the gastrointestinal tract. However, we discovered a rare phenomenon in which small cell carcinoma infiltrated the GIST of a patient. The patient came to the hospital and presented with chest tightness and shortness of breath for 2 months and a dry cough for half a month. As the ancillary tests were refined, it was discovered that he also had a lesion in the pelvic cavity. After pathological examination of the core needle biopsy (CNB) samples from the pelvic cavity lesion, the patient was diagnosed with GIST with small cell carcinoma infiltration. The patient is currently receiving a chemotherapy regimen of etoposide combined with cisplatin.
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Affiliation(s)
| | | | - Li Lyu
- Department of Pathology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Shengjie Li
- Department of Pathology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Qimin Wang
- Department of Pathology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
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Chen Y, Guo C, Cai X, Hu L, Tong X, Xue Y, Zhao Q, Zhang T, Chen Y, Fang Y, He Y, Li Y, Zhou B, Ji H. Genetic tracing uncovers the importance of epithelial-to-mesenchymal transition in small cell lung cancer chemotherapy resistance but not metastasis. Cell Discov 2024; 10:60. [PMID: 38834595 DOI: 10.1038/s41421-024-00687-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 05/03/2024] [Indexed: 06/06/2024] Open
Affiliation(s)
- Yuting Chen
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Chenchen Guo
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Xinlei Cai
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Liang Hu
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Xinyuan Tong
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Yun Xue
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Qiqi Zhao
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Tengfei Zhang
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yuan Chen
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yongting Fang
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yayi He
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yan Li
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Bin Zhou
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
- University of Chinese Academy of Sciences, Beijing, China.
| | - Hongbin Ji
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
- University of Chinese Academy of Sciences, Beijing, China.
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Meng Y, Zhang H, Xu M, Chen Z, Wei L. Regulatory mechanism and expression level of PRPS2 in lung cancer. Thorac Cancer 2024; 15:1410-1418. [PMID: 38736292 PMCID: PMC11194120 DOI: 10.1111/1759-7714.15302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/11/2024] [Accepted: 03/13/2024] [Indexed: 05/14/2024] Open
Abstract
BACKGROUND Lung cancer, with high morbidity and mortality, is the commonest respiratory system neoplasm, which seriously endangers the life safety of patients. In this study, the effect of PRPS2 on cell progression was preliminarily investigated. METHODS Immunohistochemical staining, western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to verify the expression level of PRPS2 in lung cancer. Lung cancer cell lines with stable downregulation of PRPS2 were constructed in A549 cells and NCIH460 cells. The function of PRPS2 silencing on the proliferation ability was verified by the EdU and cell colony formation experiment. Scratch and transwell tests were conducted to verify the role of PRPS2 silencing on the migratory and invasive ability of cells. The impact of PRPS2 silencing on cell apoptosis and cell cycle was verified by flow cytometry test. The effects of PRPS2 silencing on apoptosis-associated proteins were assessed by western blot assay. The function of PRPS2 silencing on tumor growth in vivo was studied through xenograft tumor experiment. RESULTS In comparison with normal tissues, PRPS2 was upregulated in lung cancer tissues. PRPS2 knockdown notably hindered the migratory ability, invasive ability and proliferation, but accelerated cell apoptosis. In vivo experiments confirmed that PRPS2 silencing blocked the growth of transplanted tumors. CONCLUSION In lung cancer, PRPS2 silencing suppressed the malignant progression, indicating that PRPS2 might be a novel biomarker for lung cancer treatment and diagnosis.
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Affiliation(s)
- Ying Meng
- Department of OncologyZibo Central HospitalZiboChina
| | - Hua Zhang
- Department of Pulmonary and Critical Care MedicineZibo Central HospitalZiboChina
| | - Mingling Xu
- Department of Pulmonary and Critical Care MedicineZibo Central HospitalZiboChina
| | - Zhenzhen Chen
- Department of Pulmonary and Critical Care MedicineZibo Central HospitalZiboChina
| | - Lei Wei
- Department of Pulmonary and Critical Care MedicineZibo Central HospitalZiboChina
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50
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Meder L, Orschel CI, Otto CJ, Koker M, Brägelmann J, Ercanoglu MS, Dähling S, Compes A, Selenz C, Nill M, Dietlein F, Florin A, Eich ML, Borchmann S, Odenthal M, Blazquez R, Hilberg F, Klein F, Hallek M, Büttner R, Reinhardt HC, Ullrich RT. Blocking the angiopoietin-2-dependent integrin β-1 signaling axis abrogates small cell lung cancer invasion and metastasis. JCI Insight 2024; 9:e166402. [PMID: 38775153 PMCID: PMC11141935 DOI: 10.1172/jci.insight.166402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 04/05/2024] [Indexed: 06/02/2024] Open
Abstract
Small cell lung cancer (SCLC) is the most aggressive lung cancer entity with an extremely limited therapeutic outcome. Most patients are diagnosed at an extensive stage. However, the molecular mechanisms driving SCLC invasion and metastasis remain largely elusive. We used an autochthonous SCLC mouse model and matched samples from patients with primary and metastatic SCLC to investigate the molecular characteristics of tumor metastasis. We demonstrate that tumor cell invasion and liver metastasis in SCLC are triggered by an Angiopoietin-2 (ANG-2)/Integrin β-1-dependent pathway in tumor cells, mediated by focal adhesion kinase/Src kinase signaling. Strikingly, CRISPR-Cas9 KO of Integrin β-1 or blocking Integrin β-1 signaling by an anti-ANG-2 treatment abrogates liver metastasis formation in vivo. Interestingly, analysis of a unique collection of matched samples from patients with primary and metastatic SCLC confirmed a strong increase of Integrin β-1 in liver metastasis in comparison with the primary tumor. We further show that ANG-2 blockade combined with PD-1-targeted by anti-PD-1 treatment displays synergistic treatment effects in SCLC. Together, our data demonstrate a fundamental role of ANG-2/Integrin β-1 signaling in SCLC cells for tumor cell invasion and liver metastasis and provide a potentially new effective treatment strategy for patients with SCLC.
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Affiliation(s)
- Lydia Meder
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Faculty of Medicine, Department of Experimental Medicine 1, Erlangen, Germany
- Mildred Scheel School of Oncology and
| | - Charlotte Isabelle Orschel
- Mildred Scheel School of Oncology and
- Department I of Internal Medicine, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Christoph Julius Otto
- Mildred Scheel School of Oncology and
- Department I of Internal Medicine, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Mirjam Koker
- Department I of Internal Medicine, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Johannes Brägelmann
- Mildred Scheel School of Oncology and
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Department of Translational Genomics and
| | - Meryem S. Ercanoglu
- Institute of Virology, Laboratory of Experimental Immunology, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
| | - Sabrina Dähling
- Institute of Virology, Laboratory of Experimental Immunology, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
| | - Anik Compes
- Mildred Scheel School of Oncology and
- Department I of Internal Medicine, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Carolin Selenz
- Department I of Internal Medicine, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Marieke Nill
- Department I of Internal Medicine, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Felix Dietlein
- Department of Medical Oncology, Dana-Faber Cancer Institute, Boston, Massachusetts, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Alexandra Florin
- Institute for Pathology, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
| | - Marie-Lisa Eich
- Institute for Pathology, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
| | - Sven Borchmann
- Department I of Internal Medicine, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
- Else Kröner Forschungskolleg Clonal Evolution in Cancer, University Hospital Cologne, Cologne, Germany
- German Hodgkin Study Group, Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
| | - Margarete Odenthal
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Institute for Pathology, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
| | - Raquel Blazquez
- University Hospital Regensburg, Department of Internal Medicine III, Hematology and Medical Oncology, Regensburg, Germany
| | - Frank Hilberg
- Department of Pharmacology, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Florian Klein
- Institute of Virology, Laboratory of Experimental Immunology, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
| | - Michael Hallek
- Department I of Internal Medicine, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
| | - Reinhard Büttner
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Institute for Pathology, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
| | - H. Christian Reinhardt
- Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, German Cancer Consortium (DKTK), Essen, Germany
| | - Roland T. Ullrich
- Mildred Scheel School of Oncology and
- Department I of Internal Medicine, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine at the University Hospital Cologne, Cologne, Germany
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