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Wu Z, Rao C, Xie Y, Ye Z, Zhang Y, Ma Z, Su Z, Ye Z. GALR1 and PENK serve as potential biomarkers in invasive non-functional pituitary neuroendocrine tumours. Gene 2025; 950:149374. [PMID: 40024300 DOI: 10.1016/j.gene.2025.149374] [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: 12/09/2024] [Revised: 02/24/2025] [Accepted: 02/26/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND Some nonfunctioning pituitary neuroendocrine tumor (NFPitNET) can show invasive growth, which increases the difficulty of surgery and indicates a poor prognosis. However, the molecular mechanism related to invasiveness remains to be further studied. This study is to screen and identify the characteristic biomarkers of invasive NFPitNETs. METHODS Based on the data of 73 NFPitNETs microarray chips in the GSE169498 dataset, this study used weighted gene co-expression network (WGCNA), differential expression analysis, protein-protein interaction (PPI) network analysis and various machine learning methods (XGBOOST, LASSO regression, random forest, support vector machine) to screen candidate biomarkers for invasive NFPitNET. Then, using gene set enrichment analysis (GSEA) to explore the differences in biological activities and signaling pathways between invasive NFPitNET and non-invasive NFPitNET. Single-sample GSEA (ssGSEA) was used to analyze key biomarkers-related signaling pathways. Finally, the expression and function of the key biomarkers were verified by q-RT PCR, immunohistochemical (IHC) experiments and in vitro experiments. RESULTS Combined with WGCNA and differential expression analysis, 128 high-expression and 85 low-expression candidate biomarkers were preliminarily obtained. PPI analysis and four machine learning algorithms further identified GALR1, PENK and HOXD9. The receiver operating characteristic (ROC) curve results showed that the three biomarkers had good predictive ability of invasiveness. After combining the validation set data, GALR1 and PENK were the final key biomarkers. Finally, PCR and IHC results verified the decreased expression of GALR1 and PENK in invasive NFPitNET and promotes proliferation and invasive ablity of pituitary tumor cells. CONCLUSION This study confirmed that the reduced expression of GALR1 and PENK is an important molecular feature of invasive NFPitNETs, which may play an important role in inhibiting the development of NFPitNET.
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Affiliation(s)
- Zerui Wu
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Changjun Rao
- Department of Cell Biology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China; Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China
| | - Yilin Xie
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Zhen Ye
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Yichao Zhang
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Zengyi Ma
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
| | - Zhipeng Su
- Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China.
| | - Zhao Ye
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China; National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
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Hu Y, Kuang M, Song H, Tan Y, Zhou F, Pei G, Jiao L. Astragaloside IV prevents liver fibrosis by blocking glycolysis-mediated macrophage M1 polarization. Eur J Pharmacol 2025; 995:177353. [PMID: 39971227 DOI: 10.1016/j.ejphar.2025.177353] [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: 12/02/2024] [Revised: 01/22/2025] [Accepted: 02/05/2025] [Indexed: 02/21/2025]
Abstract
Hepatic fibrosis is a late-stage process of many chronic liver diseases. Blocking the fibrosis process will be beneficial to the treatment and recovery of the disease. Hepatic macrophages are a remarkably heterogeneous population of immune cells that play multiple functions in homeostasis and are central to liver fibrosis. Glycolysis-mediated macrophage metabolic reprogramming leads to an increase in the proportion of M1 macrophages and the release of pro-inflammatory cytokines. The present study aimed to investigate the therapeutic effect and mechanism of Astragaloside IV (AS-IV) against carbon tetrachloride (CCl4)-induced liver fibrosis. The study found that AS-IV is an effective agent for reducing the production of inflammatory factors in CCl4-induced liver fibrosis. It was also found that AS-IV blocks macrophage M1 polarization and relieves liver fibrosis. Mechanistically, AS-IV reduces the methylation level of the FoxO1 promoter region and then upregulates its expression. FoxO1 can inhibit the expression of key enzymes in the glycolysis pathway and block glycolysis-mediated macrophage M1 polarization. Our findings indicate that AS-IV is an attractive option for treating liver fibrosis.
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Affiliation(s)
- Yutong Hu
- Hunan University of Chinese Medicine, Changsha, 410000, China; College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410000, China; Key Laboratory of Modern Research of TCM, Education Department of Hunan Province, Changsha, 410000, China.
| | - Ming Kuang
- Hunan University of Chinese Medicine, Changsha, 410000, China; College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410000, China; Key Laboratory of Modern Research of TCM, Education Department of Hunan Province, Changsha, 410000, China.
| | - Hao Song
- Hunan University of Chinese Medicine, Changsha, 410000, China; College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410000, China; Key Laboratory of Modern Research of TCM, Education Department of Hunan Province, Changsha, 410000, China.
| | - Yang Tan
- Hunan University of Chinese Medicine, Changsha, 410000, China; College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410000, China; Key Laboratory of Modern Research of TCM, Education Department of Hunan Province, Changsha, 410000, China.
| | - Feng Zhou
- Hunan University of Chinese Medicine, Changsha, 410000, China; College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410000, China; Key Laboratory of Modern Research of TCM, Education Department of Hunan Province, Changsha, 410000, China.
| | - Gang Pei
- Hunan University of Chinese Medicine, Changsha, 410000, China; College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410000, China; Key Laboratory of Modern Research of TCM, Education Department of Hunan Province, Changsha, 410000, China.
| | - Luojia Jiao
- Hunan University of Chinese Medicine, Changsha, 410000, China.
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Hu X, Li Y, Wang X, Xue X. Role of M2 macrophage-derived exosomes in cancer drug resistance via noncoding RNAs. Discov Oncol 2025; 16:741. [PMID: 40355722 PMCID: PMC12069209 DOI: 10.1007/s12672-025-02195-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 03/20/2025] [Indexed: 05/14/2025] Open
Abstract
This review summarizes recent findings on the role of M2 tumor-associated macrophages (TAMs) and their exosome-derived non-coding RNAs (ncRNAs) in cancer cell resistance to therapeutics. M2 TAMs promote angiogenesis, suppress immune responses, and facilitate metastasis, thereby creating a tumor-supporting microenvironment. A range of antitumor drugs, including 5-FU, cisplatin, and gemcitabine, are mediated by M2 exosomes, each with distinct mechanisms of action. M2 exosomes transfer drug resistance capabilities via extracellular vesicles, especially exosomes containing miRNAs, lncRNAs, and circRNAs. These exosome mediate the development of tumor drug resistance by regulating signaling pathways such as PI3K/AKT, MAPK/ERK, Wnt/β-catenin M2 exosomes can regulate cellular responses by delivering bioactive molecules, including proteins, lipids, and ncRNA, which can also modulate cellular reactions to ionizing radiation, ultraviolet light, and chemotherapeutic agents. Targeting M2 TAMs and their exosome-mediated ncRNAs may offer new strategies to overcome drug resistance in cancer.
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Affiliation(s)
- Xiaopeng Hu
- Medical Research Center, People's Hospital of Longhua, Shenzhen, 518000, China
| | - Yanhua Li
- Department of Pathology, Shenzhen Longhua Maternity and Child Healthcare Hospital, Shenzhen, 518000, China
| | - Xisheng Wang
- Medical Research Center, People's Hospital of Longhua, Shenzhen, 518000, China
| | - Xingkui Xue
- Medical Research Center, People's Hospital of Longhua, Shenzhen, 518000, China.
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4
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Shi J, Cui X, Wang J, Liu G, Meng J, Zhang Y. Crosstalk between the tumor immune microenvironment and metabolic reprogramming in pancreatic cancer: new frontiers in immunotherapy. Front Immunol 2025; 16:1564603. [PMID: 40356913 PMCID: PMC12066759 DOI: 10.3389/fimmu.2025.1564603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 04/07/2025] [Indexed: 05/15/2025] Open
Abstract
In recent years, the incidence and mortality of pancreatic cancer (PC) are increasing year by year. The highly heterogeneous nature of PC, its strong immune escape ability and easy metastasis make it the most lethal malignant tumor in the world. With the rapid development of sequencing technology, the complex components in the tumor microenvironment (TME) of PC have been gradually revealed. Interactions between pancreatic stellate cells, tumor-associated fibroblasts, various types of immune cells, and cancer cells collectively promote metabolic reprogramming of all types of cells. This metabolic reprogramming further enhances the immune escape mechanism of tumor cells and ultimately induces tumor cells to become severely resistant to chemotherapy and immunotherapy. On the one hand, PC cells achieve re and rational utilization of glucose, amino acids and lipids through metabolic reprogramming, which in turn accomplishes biosynthesis and energy metabolism requirements. Under such conditions, tumorigenesis, proliferation and metastasis are ultimately promoted. On the other hand, various types of immune cells in the tumor immune microenvironment (TIME) also undergo metabolic reprogramming, which leads to tumor progression and suppression of anti-immune responses by inhibiting the function of normal anti-tumor immune cells and enhancing the function of immunosuppressive cells. The aim of this review is to explore the interaction between the immune microenvironment and metabolic reprogramming in PC. The focus is to summarize the specific mechanisms of action of metabolic reprogramming of PC cells and metabolic reprogramming of immune cells. In addition, this review will summarize the mechanisms of immunotherapy resistance in PC cells. In the future, targeting specific mechanisms of metabolic reprogramming will provide a solid theoretical basis for the development of combination therapies for PC.
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Affiliation(s)
- Jintai Shi
- College of Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaoyan Cui
- Pharmacy Department, Jinan Huaiyin People’s Hospital, Jinan, China
| | - Junlin Wang
- Department of Pharmacy, Shandong University Second People’s Hospital, Jinan, China
| | - Guangqia Liu
- Department of Pharmacy, Jinan Licheng District Liubu Town Health Centre, Jinan, China
| | - Jiayin Meng
- Department of Pharmacy, Jinan Second People’s Hospital, Jinan, China
| | - Yingjie Zhang
- College of Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
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5
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Tataranu LG. A Nexus of Biomolecular Complexities in Pituitary Neuroendocrine Tumors: Insights into Key Molecular Drivers. Biomedicines 2025; 13:968. [PMID: 40299639 PMCID: PMC12024600 DOI: 10.3390/biomedicines13040968] [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: 02/15/2025] [Revised: 03/10/2025] [Accepted: 03/17/2025] [Indexed: 05/01/2025] Open
Abstract
Approximately 90% of the lesions of hypophyseal origins are represented by pituitary neuroendocrine tumors, which further account for up to 22.5% of the intracranial tumors in the adult population. Although the intricacy of this pathology is yet to be fully understood on a biomolecular level, it is well known that these lesions develop within a microenvironment that supports their evolution and existence. The role of the tumoral microenvironment in pituitary lesions is pivotal, mainly due to this gland's distinct anatomical, histological, and physiological structure and function. Each component of the tumoral microenvironment is specifically involved in tumorigenesis, angiogenesis, tumoral growth, progression, and dissemination. By recognizing and understanding how these elements are involved in such processes, targeted treatments can emerge, and better future management of pituitary lesions can be provided. This article aims to summarize the role of each component of the tumoral microenvironment in pituitary lesions while assessing their association with biomolecular mechanisms.
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Affiliation(s)
- Ligia Gabriela Tataranu
- Department of Neurosurgery, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania;
- Department of Neurosurgery, Bagdasar-Arseni Emergency Clinical Hospital, 041915 Bucharest, Romania
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Guan Y, Zhang M, Song J, Negrete M, Adcock T, Kandel R, Racioppi L, Gerecht S. CaMKK2 Regulates Macrophage Polarization Induced by Matrix Stiffness: Implications for Shaping the Immune Response in Stiffened Tissues. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2417778. [PMID: 40036145 PMCID: PMC12021110 DOI: 10.1002/advs.202417778] [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: 12/30/2024] [Revised: 01/13/2025] [Indexed: 03/06/2025]
Abstract
Macrophages are essential for immune responses and maintaining tissue homeostasis, exhibiting a wide range of phenotypes depending on their microenvironment. The extracellular matrix (ECM) is a vital component that provides structural support and organization to tissues, with matrix stiffness acting as a key regulator of macrophage behavior. Using physiologically relevant 3D stiffening hydrogel models, it is found that increased matrix stiffness alone promoted macrophage polarization toward a pro-regenerative phenotype, mimicking the effect of interleukin-4(IL-4) in softer matrices. Blocking Calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) selectively inhibited stiffness-induced macrophage polarization without affecting IL-4-driven pro-regenerative pathways. In functional studies, CaMKK2 deletion prevented M2-like/pro-tumoral polarization caused by matrix stiffening, which in turn hindered tumor growth. In a murine wound healing model, loss of CaMKK2 impaired matrix stiffness-mediated macrophage accumulation, ultimately disrupting vascularization. These findings highlight the critical role of CaMKK2 in the macrophage mechanosensitive fate determination and gene expression program, positioning this kinase as a promising therapeutic target to selectively modulate macrophage responses in pathologically stiff tissues.
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Affiliation(s)
- Ya Guan
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Min Zhang
- Division of Hematological Malignancies and Cellular TherapyDepartment of MedicineDuke University Medical CenterDurhamNC27708USA
| | - Jiyeon Song
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Marcos Negrete
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Tyler Adcock
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
| | - Reeva Kandel
- Division of Hematological Malignancies and Cellular TherapyDepartment of MedicineDuke University Medical CenterDurhamNC27708USA
| | - Luigi Racioppi
- Division of Hematological Malignancies and Cellular TherapyDepartment of MedicineDuke University Medical CenterDurhamNC27708USA
- Department of Molecular Medicine and Medical BiotechnologyUniversity of Naples Federico IINaplesItaly
| | - Sharon Gerecht
- Department of Biomedical EngineeringDuke UniversityDurhamNC27708USA
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Ma J, Tang L, Xiao J, Tang K, Zhang H, Huang B. Burning lactic acid: a road to revitalizing antitumor immunity. Front Med 2025:10.1007/s11684-025-1126-6. [PMID: 40119026 DOI: 10.1007/s11684-025-1126-6] [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: 07/31/2024] [Accepted: 12/16/2024] [Indexed: 03/24/2025]
Abstract
Lactic acid (LA) accumulation in tumor microenvironments (TME) has been implicated in immune suppression and tumor progress. Diverse roles of LA have been elucidated, including microenvironmental pH regulation, signal transduction, post-translational modification, and metabolic remodeling. This review summarizes LA functions within TME, focusing on the effects on tumor cells, immune cells, and stromal cells. Reducing LA levels is a potential strategy to attack cancer, which inevitably affects the physiological functions of normal tissues. Alternatively, transporting LA into the mitochondria as an energy source for immune cells is intriguing. We underscore the significance of LA in both tumor biology and immunology, proposing the burning of LA as a potential therapeutic approach to enhance antitumor immune responses.
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Affiliation(s)
- Jingwei Ma
- Department of Immunology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China.
| | - Liang Tang
- Department of Immunology & State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China
| | - Jingxuan Xiao
- Department of Immunology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China
| | - Ke Tang
- Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China
| | - Huafeng Zhang
- Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bo Huang
- Department of Immunology & State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China.
- Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China.
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8
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Lan Q, Ouyang A, Chen Y, Li Y, Zhong B, Deng S. Pain, lactate, and anesthetics: intertwined regulators of tumor metabolism and immunity. Front Oncol 2025; 15:1534300. [PMID: 40165895 PMCID: PMC11955471 DOI: 10.3389/fonc.2025.1534300] [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: 11/25/2024] [Accepted: 02/24/2025] [Indexed: 04/02/2025] Open
Abstract
Patients with advanced cancer frequently endure severe pain, which substantially diminishes their quality of life and can adversely impact survival. Analgesia, a critical modality for alleviating such pain, is now under scrutiny for its potential role in cancer progression, a relationship whose underlying mechanisms remain obscure. Emerging evidence suggests that lactate, once considered a metabolic byproduct, actively participates in the malignant progression of cancer by modulating both metabolic and immunological pathways within the tumor microenvironment. Furthermore, lactate is implicated in the modulation of cancer-related pain, exerting effects through direct and indirect mechanisms. This review synthesizes current understanding of lactate's production, transport, and functional roles in tumor cells, encompassing the regulation of tumor metabolism, immunity, and progression. Additionally, we dissect the complex, bidirectional relationship between lactate and pain, and assess the impact of anesthetics on pain relief, lactate homeostasis, and tumorigenesis.
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Affiliation(s)
| | | | | | | | | | - Simin Deng
- Department of Anesthesiology, Ganzhou People's Hospital, Ganzhou, Jiangxi, China
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9
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Liu W, Sun Y, Zhang Y, Yin D. The causal relationships between inflammatory cytokines, blood metabolites, and thyroid cancer: a two-step Mendelian randomization analysis. Discov Oncol 2025; 16:301. [PMID: 40072746 PMCID: PMC11904021 DOI: 10.1007/s12672-025-02029-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Thyroid cancer is a prevalent malignant tumor, especially with a higher incidence in women. Tumor microenvironment changes induced by inflammation and alterations in metabolic characteristics are critical in the development of thyroid cancer. Nevertheless, their causal relationships remain unclear. METHODS We utilized thyroid cancer GWAS data from the Global Biobank Meta-Analysis Initiative and GWAS data of 91 inflammatory cytokines and 1400 blood metabolites obtained from the GWAS Catalog to evaluate the causality between inflammatory cytokines, blood metabolites, and thyroid cancer using Mendelian randomization (MR). Initially, we identified inflammatory cytokines having a significant causal effect on thyroid cancer. Subsequently, for the identified positive blood metabolites, we applied a two-step mediation MR method to examine their mediating role in the causal effect of specific inflammatory cytokines on thyroid cancer. RESULTS Our forward MR analysis identified suggestive associations between 7 inflammatory cytokines and thyroid cancer risks, and found that tumor necrosis factor ligand superfamily member 14 (TNFSF14) (IVW-OR: 1.25, 95% CI 1.10-1.42, p = 0.0004) is a significant risk factor in thyroid cancer, and this causal relationship remained significant after Bonferroni correction. The reverse MR analysis identified suggestive causal associations between thyroid cancer and 3 inflammatory cytokines and ruled out the reverse causality between TNFSF14 and thyroid cancer. Then, we identified suggestive associations between 35 blood metabolites and 24 blood metabolite ratios with thyroid cancer, and found that 5-hydroxymethyl-2-furoylcarnitine (IVW-OR: 1.38, 95% CI 1.19-1.61, p = 0.00003) is a significant risk factor for thyroid cancer, with this causality remaining significant after Bonferroni correction. Finally, our two-step MR analysis indicated that Lactosyl-N-palmitoyl-sphingosine (d18:1/16:0) and X-12013 have a mediating effect in the causal relationship between TNFSF14 and thyroid cancer, with mediation proportions of 8.55% and 5.78%, respectively. Our MR analysis did not identify significant heterogeneity or horizontal pleiotropy. CONCLUSION This study identified some inflammatory cytokines and blood metabolites associated with thyroid cancer risk and revealed the mediating role of specific blood metabolites between TNFSF14 and thyroid cancer, highlighting the critical role of inflammatory and metabolic pathways in the pathogenesis of thyroid cancer.
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Affiliation(s)
- Weihao Liu
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yuxiao Sun
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yifei Zhang
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Detao Yin
- Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Engineering Research Center of Multidisciplinary Diagnosis and Treatment of Thyroid Cancer of Henan Province, Zhengzhou, 450052, China.
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10
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Ding X, Mei T, Xi X, Wang J, Wang W, Chen Y, Lu Y, Qin T, Huang D. ACT001 Suppresses the Malignant Progression of Small-Cell Lung Cancer by Inhibiting Lactate Production and Promoting Anti-Tumor Immunity. Thorac Cancer 2025; 16:e70028. [PMID: 40016971 PMCID: PMC11868026 DOI: 10.1111/1759-7714.70028] [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: 10/09/2024] [Revised: 02/12/2025] [Accepted: 02/16/2025] [Indexed: 03/01/2025] Open
Abstract
BACKGROUND Improving the "cold" tumor immune microenvironment (TIME) of small-cell lung cancer (SCLC) represents a promising therapeutic approach. The metabolite lactate plays a crucial role in shaping the immune-cold tumor microenvironment (TME) and facilitating tumor progression. Phosphoglycerate kinase 1 (PGK1) is a key enzyme involved in tumor lactate metabolism. This study demonstrates that ACT001 improves the TIME of SCLC through inhibiting lactate production by targeting PGK1. METHODS The cytotoxic effects of ACT001 on SCLC cell lines NCI-H1688 and NCI-H446 were evaluated using MTT assay, clone formation, EdU incorporation, wound healing, and invasion assays. To elucidate the mechanism of action of ACT001, proteomic techniques, pull-down assays, LC-MS/MS, surface plasmon resonance, immunofluorescence, lactate generation, glucose uptake, and western blot assays were conducted. A xenograft model was used to assess the in vivo anti-tumor activity of ACT001. RESULTS ACT001 inhibited the proliferation, invasion, and metastasis of SCLC both in vitro and in vivo. Additionally, it reduced lactate accumulation and M2 macrophage polarization. Mechanistically, ACT001 released micheliolide, which covalently modified Cys316 of PGK1 under physiological conditions. This suppressed PGK1 activity and restored the distribution of PGK1 in mitochondria and the cytoplasm under hypoxic conditions. CONCLUSIONS ACT001 inhibits the malignant progression of SCLC by suppressing lactate production, modulating macrophage polarization, and restraining tumor metastasis through PGK1 targeting.
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Affiliation(s)
| | - Ting Mei
- National Clinical Research Center for CancerTianjin Medical University Cancer Institute & HospitalTianjinChina
- Key Laboratory of Cancer Prevention and TherapyTianjinChina
- Tianjin's Clinical Research Center for CancerTianjinChina
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & HospitalTianjin Medical UniversityTianjinChina
| | - Xiao‐Nan Xi
- College of PharmacyNankai UniversityTianjinChina
- State Key Laboratory of Medicinal Chemical BiologyNankai UniversityTianjinChina
| | - Jing‐Ya Wang
- National Clinical Research Center for CancerTianjin Medical University Cancer Institute & HospitalTianjinChina
- Key Laboratory of Cancer Prevention and TherapyTianjinChina
- Tianjin's Clinical Research Center for CancerTianjinChina
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & HospitalTianjin Medical UniversityTianjinChina
| | | | - Yue Chen
- State Key Laboratory of Medicinal Chemical BiologyNankai UniversityTianjinChina
- College of ChemistryNankai UniversityTianjinChina
| | - Ya‐Xin Lu
- State Key Laboratory of Medicinal Chemical BiologyNankai UniversityTianjinChina
- College of ChemistryNankai UniversityTianjinChina
| | - Ting‐Ting Qin
- National Clinical Research Center for CancerTianjin Medical University Cancer Institute & HospitalTianjinChina
- Key Laboratory of Cancer Prevention and TherapyTianjinChina
- Tianjin's Clinical Research Center for CancerTianjinChina
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & HospitalTianjin Medical UniversityTianjinChina
| | - Ding‐Zhi Huang
- National Clinical Research Center for CancerTianjin Medical University Cancer Institute & HospitalTianjinChina
- Key Laboratory of Cancer Prevention and TherapyTianjinChina
- Tianjin's Clinical Research Center for CancerTianjinChina
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & HospitalTianjin Medical UniversityTianjinChina
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11
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Zou R, Jiang S, Mei J, Chen C, Yu J, Fu Y, Chen S. High-ammonia microenvironment promotes stemness and metastatic potential in hepatocellular carcinoma through metabolic reprogramming. Discov Oncol 2025; 16:182. [PMID: 39953190 PMCID: PMC11828779 DOI: 10.1007/s12672-025-01922-8] [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: 11/11/2024] [Accepted: 02/04/2025] [Indexed: 02/17/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a prevalent and aggressive form of liver cancer, characterized by frequent recurrence and metastasis, which remain significant obstacles to effective treatment. Ammonia accumulates in the tumor microenvironment of HCC due to dysfunction in the urea cycle, but the detailed impact of ammonia on HCC cells remains insufficiently understood. METHODS We exposed HCC cell lines to high concentrations of ammonium chloride to evaluate alterations in proliferation, stemness, and migratory potential. After ammonia removal, changes in cellular behavior were assessed using colony formation, and spheroid assays. Transcriptomic and metabolomic analyses were conducted to investigate ammonia-induced metabolic reprogramming and alterations in gene expression. Additionally, animal models were employed to validate the impact of ammonia on tumor growth and metastasis. RESULTS Exposure to high-ammonia conditions transiently suppressed HCC cell proliferation without inducing apoptosis. However, following ammonia removal, cells demonstrated increased proliferation, enhanced spheroid formation, and elevated migratory capacity. Transcriptomic analysis revealed the upregulation of genes associated with cell adhesion, migration, and glycolysis. Concurrently, metabolomic profiling indicated increased lactate production, facilitating the aggressive behavior of HCC cells after ammonia withdrawal. Animal experiments confirmed that high-ammonia exposure accelerated tumor growth and metastasis. CONCLUSION Ammonia exerts a dual effect on HCC progression: it initially suppresses cell growth but later promotes stemness, proliferation, and metastasis through metabolic reprogramming. Targeting ammonia metabolism or glycolysis in the tumor microenvironment may represent a promising therapeutic strategy for mitigating HCC recurrence and metastasis. Future studies utilizing clinical samples are required to validate these findings and identify potential therapeutic strategies targeting ammonia metabolism.
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Affiliation(s)
- Renchao Zou
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Sicong Jiang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiaqi Mei
- Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chen Chen
- Department of Magnetic Resonance, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jia Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanqiu Fu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Siyu Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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12
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Zhao RJ, Fan XX. Advances in Antibody-Based Immune-Stimulating Drugs: Driving Innovation in Cancer Therapy. Int J Mol Sci 2025; 26:1440. [PMID: 40003906 PMCID: PMC11855211 DOI: 10.3390/ijms26041440] [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: 01/19/2025] [Revised: 02/05/2025] [Accepted: 02/07/2025] [Indexed: 02/27/2025] Open
Abstract
Antibody-based immune-stimulating drugs (ABIs) represent a transformative frontier in cancer immunotherapy, designed to reshape the tumor microenvironment and overcome immune suppression. This study highlighted recent advances in ABIs, including immune-stimulating antibody conjugates (ISACs), bispecific antibodies (BsAbs), and checkpoint blockade enhancers, with a focus on their mechanisms of action, clinical advancements, and challenges. Preclinical findings revealed that ISACs effectively boost overall anti-cancer immunity by reprogramming tumor-associated macrophages, enhancing T cell activation, and engaging other immune pathways. Similarly, BsAbs effectively redirect immune cells to tumors, achieving significant tumor regression. Additionally, artificial intelligence (AI) is revolutionizing the development of ABIs by optimizing drug design, identifying novel targets, and accelerating preclinical validation, enabling personalized therapeutic strategies. Despite these advancements, significant challenges remain, including immune resistance and off-target effects. Future research should prioritize next-generation multifunctional antibodies, AI-driven innovations, and combination therapies to enhance efficacy and expand therapeutic applications. Connecting these gaps could unlock the full potential of ABIs, upgrading cancer treatment and improving outcomes for patients with refractory or resistant tumors.
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Affiliation(s)
| | - Xing-Xing Fan
- Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau SAR 999078, China
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13
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Zeng Y, Huang Y, Tan Q, Peng L, Wang J, Tong F, Dong X. Influence of lactate in resistance to anti‑PD‑1/PD‑L1 therapy: Mechanisms and clinical applications (Review). Mol Med Rep 2025; 31:48. [PMID: 39670310 DOI: 10.3892/mmr.2024.13413] [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: 08/29/2024] [Accepted: 11/01/2024] [Indexed: 12/14/2024] Open
Abstract
Metabolic reprogramming is a prominent characteristic of tumor cells, evidenced by heightened secretion of lactate, which is linked to tumor progression. Furthermore, the accumulation of lactate in the tumor microenvironment (TME) influences immune cell activity, including the activity of macrophages, dendritic cells and T cells, fostering an immunosuppressive milieu. Anti‑programmed cell death protein 1 (PD‑1)/programmed death‑ligand 1 (PD‑L1) therapy is associated with a prolonged survival time of patients with non‑small cell lung cancer. However, some patients still develop resistance to anti‑PD‑1/PD‑L1 therapy. Lactate is associated with resistance to anti‑PD‑1/PD‑L1 therapy. The present review summarizes what is known about lactate metabolism in tumor cells and how it affects immune cell function. In addition, the present review emphasizes the relationship between lactate secretion and immunotherapy resistance. The present review also explores the potential for targeting lactate within the TME to enhance the efficacy of immunotherapy.
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Affiliation(s)
- Yi Zeng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yu Huang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Qiaoyun Tan
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Ling Peng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jian Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Fan Tong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Xiaorong Dong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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14
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Liu H, Wang P, Li J, Zhao J, Mu Y, Gu W. Role of Cathepsin K in bone invasion of pituitary adenomas: A dual mechanism involving cell proliferation and osteoclastogenesis. Cancer Lett 2025; 611:217443. [PMID: 39755363 DOI: 10.1016/j.canlet.2025.217443] [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: 09/04/2024] [Revised: 12/26/2024] [Accepted: 01/01/2025] [Indexed: 01/06/2025]
Abstract
This study aimed to investigate the regulation and underlying mechanism of Cathepsin K (CTSK) in bone-invasive pituitary adenomas (BIPAs). A total of 1437 patients with pituitary adenomas were included and followed up. RNA sequencing, immunohistochemistry, and qRT-PCR were used to analyze CTSK expression. The effects of CTSK on cellular proliferation, bone matrix degradation, and osteoclast differentiation were determined by gain/loss of function experiments in vitro and in vivo. The exploration of signaling pathways was determined through molecular biology experiments. Here, we reported a significant fraction (∼10 %) of pituitary adenoma patients developed bone invasion, which was correlated with tumor recurrence. Patients with BIPAs had shorter recurrence-free survival. CTSK expression was increased in BIPA patients and was strongly associated with a worse prognosis. Increased CTSK expression enhanced pituitary adenoma cell proliferation through the activation of the mammalian target of rapamycin (mTOR) signaling pathway and promoted bone invasion by increasing osteoclast differentiation both in vitro and in vivo. Treatment with the CTSK inhibitor odanacatib effectively inhibited pituitary adenoma cell proliferation and bone invasion in these models. Additionally, CTSK facilitated osteoclast differentiation by promoting RANKL expression in MC3T3-E1 cells via interaction with TLR4. Based on these findings, we conclude that CTSK has the potential to become a novel predictive biomarker and therapeutic target for BIPAs.
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Affiliation(s)
- Hongyan Liu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China; Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, 100191, China
| | - Peng Wang
- Department of Neurosurgery, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Jie Li
- Department of Pathology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Jian Zhao
- Department of Endocrinology, The 908th Hospital of Chinese PLA Joint Logistic Support Force, Nanchang, China
| | - Yiming Mu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China.
| | - Weijun Gu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China.
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15
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Song L, Yu X, Wu Y, Zhang W, Zhang Y, Shao Y, Hou Z, Yang C, Gao Y, Zhao Y. Integrin β8 Facilitates Macrophage Infiltration and Polarization by Regulating CCL5 to Promote LUAD Progression. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2406865. [PMID: 39535362 PMCID: PMC11727125 DOI: 10.1002/advs.202406865] [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: 06/20/2024] [Revised: 10/21/2024] [Indexed: 11/16/2024]
Abstract
The tumor microenvironment (TME) influences cancer progression and metastasis. Integrin β8 (ITGβ8), a member of the integrin family, is upregulated in various cancers. In this study, it is determined as a key factor that mediates the interaction between lung adenocarcinoma (LUAD) cells and macrophages. Increased expression levels of ITGβ8 are associated with increased numbers of CD163+ macrophages and poor prognosis in LUAD patients. The overexpression of ITGβ8 in LUAD cells promotes the polarization of THP-1 macrophages toward the M2 phenotype. In contrast, TCM (conditioned medium from the co-culture system) from THP-1 macrophages and ITGβ8-overexpressing A549 cells promoted the proliferation and invasion of A549 cells. Mechanistically, chemokine (C-C motif) ligand 5 (CCL5) plays an important role in mediating ITGβ8-induced macrophage polarization, and the phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT)/interferon regulatory factor 9 (IRF9) pathway is involved in this process. Moreover, interleukin 8 (IL8) and interleukin 10 (IL10) produced by M2-like macrophages regulate the expression of ITGβ8 in LUAD cells through the spi-1 proto-oncogene (SPI1). This study elucidates the feedback mechanism of ITGβ8 between LUAD cells and macrophages.
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Affiliation(s)
- Lei Song
- Department of Internal Medical OncologyHarbin Medical University Cancer HospitalHarbinHeilongjiang150081China
| | - Xi Yu
- Department of Gynecological OncologyHarbin Medical University Cancer HospitalHarbinHeilongjiang150081China
| | - Yang Wu
- Department of Breast SurgeryHarbin Medical University Cancer HospitalHarbinHeilongjiang150081China
| | - Wenwen Zhang
- Department of Gynecological OncologyHarbin Medical University Cancer HospitalHarbinHeilongjiang150081China
| | - Yu Zhang
- Department of Internal Medical OncologyHarbin Medical University Cancer HospitalHarbinHeilongjiang150081China
| | - Yanchi Shao
- Department of Internal Medical OncologyHarbin Medical University Cancer HospitalHarbinHeilongjiang150081China
| | - Zhenxin Hou
- Department of Internal Medical OncologyHarbin Medical University Cancer HospitalHarbinHeilongjiang150081China
| | - Chen Yang
- Department of Internal Medical OncologyHarbin Medical University Cancer HospitalHarbinHeilongjiang150081China
| | - Yue Gao
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiang150081China
| | - Yanbin Zhao
- Department of Internal Medical OncologyHarbin Medical University Cancer HospitalHarbinHeilongjiang150081China
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16
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Buzaglo GBB, Telles GD, Araújo RB, Junior GDS, Ruberti OM, Ferreira MLV, Derchain SFM, Vechin FC, Conceição MS. The Therapeutic Potential of Physical Exercise in Cancer: The Role of Chemokines. Int J Mol Sci 2024; 25:13740. [PMID: 39769501 PMCID: PMC11678861 DOI: 10.3390/ijms252413740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 09/25/2024] [Accepted: 09/26/2024] [Indexed: 01/11/2025] Open
Abstract
The global increase in cancer cases and mortality has been associated with inflammatory processes, in which chemokines play crucial roles. These molecules, a subfamily of cytokines, are essential for the migration, adhesion, interaction, and positioning of immune cells throughout the body. Chemokines primarily originate in response to pathogenic stimuli and inflammatory cytokines. They are expressed by lymphocytes in the bloodstream and are divided into four classes (CC, CXC, XC, and CX3C), playing multifaceted roles in the tumor environment (TME). In the TME, chemokines regulate immune behavior by recruiting cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), which promote tumor survival. Additionally, they directly influence tumor behavior, promoting pathological angiogenesis, invasion, and metastasis. On the other hand, chemokines can also induce antitumor responses by mobilizing CD8+ T cells and natural killer (NK) cells to the tumor, reducing pro-inflammatory chemokines and enhancing essential antitumor responses. Given the complex interaction between chemokines, the immune system, angiogenic factors, and metastasis, it becomes evident how important it is to target these pathways in therapeutic interventions to counteract cancer progression. In this context, physical exercise emerges as a promising strategy due to its role modulating the expression of anti-inflammatory chemokines and enhancing the antitumor response. Aerobic and resistance exercises have been associated with a beneficial inflammatory profile in cancer, increased infiltration of CD8+ T cells in the TME, and improvement of intratumoral vasculature. This creates an environment less favorable to tumor growth and supports the circulation of antitumor immune cells and chemokines. Therefore, understanding the impact of exercise on the expression of chemokines can provide valuable insights for therapeutic interventions in cancer treatment and prevention.
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Affiliation(s)
- Glenda B. B. Buzaglo
- Health Sciences Postgraduate Program, São Francisco University, Av. São Francisco de Assis, 218, Bragança Paulista, Sao Paulo 12916-900, Brazil; (G.B.B.B.); (R.B.A.); (G.D.S.J.); (O.M.R.); (M.L.V.F.)
| | - Guilherme D. Telles
- School of Physical Education and Sport, University of Sao Paulo, Sao Paulo 05508-030, Brazil; (G.D.T.); (F.C.V.)
| | - Rafaela B. Araújo
- Health Sciences Postgraduate Program, São Francisco University, Av. São Francisco de Assis, 218, Bragança Paulista, Sao Paulo 12916-900, Brazil; (G.B.B.B.); (R.B.A.); (G.D.S.J.); (O.M.R.); (M.L.V.F.)
| | - Gilmar D. S. Junior
- Health Sciences Postgraduate Program, São Francisco University, Av. São Francisco de Assis, 218, Bragança Paulista, Sao Paulo 12916-900, Brazil; (G.B.B.B.); (R.B.A.); (G.D.S.J.); (O.M.R.); (M.L.V.F.)
| | - Olivia M. Ruberti
- Health Sciences Postgraduate Program, São Francisco University, Av. São Francisco de Assis, 218, Bragança Paulista, Sao Paulo 12916-900, Brazil; (G.B.B.B.); (R.B.A.); (G.D.S.J.); (O.M.R.); (M.L.V.F.)
| | - Marina L. V. Ferreira
- Health Sciences Postgraduate Program, São Francisco University, Av. São Francisco de Assis, 218, Bragança Paulista, Sao Paulo 12916-900, Brazil; (G.B.B.B.); (R.B.A.); (G.D.S.J.); (O.M.R.); (M.L.V.F.)
| | - Sophie F. M. Derchain
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo 13083-881, Brazil;
| | - Felipe C. Vechin
- School of Physical Education and Sport, University of Sao Paulo, Sao Paulo 05508-030, Brazil; (G.D.T.); (F.C.V.)
| | - Miguel S. Conceição
- Health Sciences Postgraduate Program, São Francisco University, Av. São Francisco de Assis, 218, Bragança Paulista, Sao Paulo 12916-900, Brazil; (G.B.B.B.); (R.B.A.); (G.D.S.J.); (O.M.R.); (M.L.V.F.)
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17
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Yao Z, Chen H. Everolimus in pituitary tumor: a review of preclinical and clinical evidence. Front Endocrinol (Lausanne) 2024; 15:1456922. [PMID: 39736867 PMCID: PMC11682973 DOI: 10.3389/fendo.2024.1456922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Accepted: 11/27/2024] [Indexed: 01/01/2025] Open
Abstract
Although pituitary tumors (PTs) are mostly benign, some PTs are characterized by low surgical resection rates, high recurrence rates, and poor response to conventional treatments and profoundly affect patients' quality of life. Everolimus (EVE) is the only FDA-approved mTOR inhibitor, which can be used for oral treatment. It effectively inhibits tumor cell proliferation and angiogenesis. It has been administered for various neuroendocrine tumors of the digestive tract, lungs, and pancreas. EVE not only suppresses the growth and proliferation of APT cells but also enhances their sensitivity to radiotherapy and chemotherapy. This review introduces the role of the PI3K/AKT/mTOR pathway in the development of APTs, comprehensively explores the current status of preclinical and clinical research of EVE in APTs, and discusses the blood-brain barrier permeability and safety of EVE.
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Affiliation(s)
- Zihong Yao
- The Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China
- Department of Endocrinology and Metabolism, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Hui Chen
- Department of Endocrinology and Metabolism, Lanzhou University Second Hospital, Lanzhou, Gansu, China
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18
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Potthoff TE, Walter C, Jeising D, Münter D, Verma A, Suero Molina E, Stummer W, Dugas M, Hartmann W, Dottermusch M, Altendorf L, Schüller U, Scheuermann S, Seitz C, Albert TK, Kerl K. Single-cell transcriptomics link gene expression signatures to clinicopathological features of gonadotroph and lactotroph PitNET. J Transl Med 2024; 22:1027. [PMID: 39548496 PMCID: PMC11566263 DOI: 10.1186/s12967-024-05821-4] [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: 02/29/2024] [Accepted: 10/31/2024] [Indexed: 11/18/2024] Open
Abstract
BACKGROUND Pituitary neuroendocrine tumors (PitNET) are among the most common intracranial tumors. Despite a frequent benign course, aggressive behavior can occur. Tumor behavior is known to be under the influence of the tumor microenvironment (TME). However, the relationship between TME cells and aggressive tumor behavior has not been adequately explored in PitNET. METHODS We performed differential expression analysis as well as gene expression program identification based on single-cell RNA sequencing to comparatively characterize the transcriptome of seven gonadotroph and three lactotroph PitNET and correlate it with clinical features using bulk RNA-seq data from an independent cohort of 134 PitNET. Tumor immune infiltration was quantified via immunostaining on tissue sections of gonadotroph and lactotroph PitNET. RESULTS In lactotroph PitNET, we detect a highly proliferative gene profile with significantly increased expression levels in aggressively growing tumors within bulk RNA-seq data of an independent cohort of 134 PitNET samples. We also report high intratumoral heterogeneity in gonadotroph PitNET (GoPN) and lactotroph PitNET (LaPN) and identify signatures of epithelial, endocrine, and immunological gene networks in both subtypes. A comparison of their TME composition shows enrichment of SPP1+ macrophages and CD4+ T cells in GoPN, as well as enrichment of CD4/CD8 double-negative T cells (DN) and natural killer cells (NK) in LaPN. Also notable is the presence of proliferative lymphocytes, the occurrence of which positively correlates with more aggressive tumor behavior in the bulk RNA-seq cohort. However, increased CD8+ T and NK cell abundances correlate significantly with reduced aggressiveness indicating potential anti-tumoral effects. CONCLUSIONS Our study expands the knowledge of the differences in cellular composition of gonadotroph and lactotroph PitNET subtypes. It lays the foundation for further studies on the influence of lymphoid cells on the variable aggressive behavior of PitNET. Regarding the treatment of drug-resistant lactotroph PitNET, proliferative lymphocytes, CD8+ T, and NK cells could represent potentially valuable targets for developing new cancer immunotherapies.
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Affiliation(s)
- T Elise Potthoff
- Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Carolin Walter
- Institute of Medical Informatics, University of Münster, 48149, Münster, Germany
| | - Daniela Jeising
- Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Daniel Münter
- Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Archana Verma
- Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Eric Suero Molina
- Department of Neurosurgery, University Hospital of Münster, 48149, Münster, Germany
| | - Walter Stummer
- Department of Neurosurgery, University Hospital of Münster, 48149, Münster, Germany
| | - Martin Dugas
- Institute of Medical Informatics, University of Münster, 48149, Münster, Germany
- Institute of Medical Informatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Wolfgang Hartmann
- Division of Translational Pathology, Gerhard Domagk Institute of Pathology, University Hospital Münster, 48149, Münster, Germany
| | - Matthias Dottermusch
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany
| | - Lea Altendorf
- Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany
- Research Institute Children's Cancer Center, 20251, Hamburg, Germany
| | - Ulrich Schüller
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany
- Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany
- Research Institute Children's Cancer Center, 20251, Hamburg, Germany
| | - Sophia Scheuermann
- DFG Cluster of Excellence 2180 'Image-Guided and Functional Instructed Tumor Therapy' (iFIT), University of Tübingen, 72076, Tübingen, Germany
- Department of Pediatric Hematology and Oncology, University Hospital Tübingen, 72076, Tübingen, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site, Tuebingen, Germany
| | - Christian Seitz
- DFG Cluster of Excellence 2180 'Image-Guided and Functional Instructed Tumor Therapy' (iFIT), University of Tübingen, 72076, Tübingen, Germany
- Department of Pediatric Hematology and Oncology, University Hospital Tübingen, 72076, Tübingen, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site, Tuebingen, Germany
| | - Thomas K Albert
- Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Kornelius Kerl
- Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
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19
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Zhang F, Gu T, Li J, Zhu Y, Chu M, Zhou Q, Liu J. Emodin regulated lactate metabolism by inhibiting MCT1 to delay non-small cell lung cancer progression. Hum Cell 2024; 38:11. [PMID: 39465441 DOI: 10.1007/s13577-024-01140-4] [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: 06/25/2024] [Accepted: 09/09/2024] [Indexed: 10/29/2024]
Abstract
Lung cancer is one of the most common malignant tumors in the world, with high incidence rate and mortality. Monocarboxylate transporter (MCT) 1 has been found to be widely expressed in various tumors and plays a crucial role in regulating energy metabolism. Emodin, as an important traditional Chinese medicine in China, has been reported to inhibit the progression of lung cancer. However, its potential mechanism has not been fully elucidated. The effects of emodin and MCT1 inhibitor AZD3965 on the proliferation, migration, and invasion of lung cancer cells were detected using cell counting kit-8 (CCK-8) assay, wound-healing assay, and transwell small chamber assay. The content of glucose, lactate, and pyruvate in the cell culture medium was detected using a glucose, lactate, and pyruvate detection kit, and also detected protein expression using western blotting. In addition, to investigate the effects of emodin and AZD3965 on lung cancer in vivo, we constructed nude mice subcutaneous transplant tumor model by subcutaneous injection of lung cancer cells. The results showed that emodin and AZD3965 could inhibit the proliferation, migration, and invasion of lung cancer cells. At the same time, they could inhibit the expression of MCT1 in lung cancer cells and promote the release of lactate, but did not affect the content of glucose and pyruvate. In vivo experiments had shown that emodin and AZD3965 could effectively inhibit the growth of lung cancer and inhibit the expression of MCT1. All in all, our data suggested that emodin inhibited the proliferation, migration, and invasion of lung cancer cells, possibly by inhibiting MCT1, providing important theoretical basis for elucidating the mechanism of emodin in treating lung cancer.
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Affiliation(s)
- Fei Zhang
- First Affiliated Hospital of Guizhou, University of Traditional Chinese Medicine, Guiyang, 550001, China
| | - Tian Gu
- First Affiliated Hospital of Guizhou, University of Traditional Chinese Medicine, Guiyang, 550001, China
| | - Jin Li
- First Affiliated Hospital of Guizhou, University of Traditional Chinese Medicine, Guiyang, 550001, China
| | - Yanqiu Zhu
- First Affiliated Hospital of Guizhou, University of Traditional Chinese Medicine, Guiyang, 550001, China
| | - Mingliang Chu
- First Affiliated Hospital of Guizhou, University of Traditional Chinese Medicine, Guiyang, 550001, China.
| | - Qing Zhou
- First Affiliated Hospital of Guizhou, University of Traditional Chinese Medicine, Guiyang, 550001, China.
| | - Jiemin Liu
- Department of Endoscopy, Guizhou Provincial People's Hospital, Guiyang, 550002, China.
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20
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Fan Q, Fu ZW, Xu M, Lv F, Shi JS, Zeng QQ, Xiong DH. Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer. World J Gastrointest Oncol 2024; 16:4064-4079. [DOI: 10.4251/wjgo.v16.i10.4064] [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: 06/05/2024] [Revised: 08/03/2024] [Accepted: 08/16/2024] [Indexed: 09/26/2024] Open
Abstract
The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
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Affiliation(s)
- Qi Fan
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Zheng-Wei Fu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Ming Xu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Feng Lv
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Jia-Song Shi
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Qi-Qi Zeng
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - De-Hai Xiong
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
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21
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Liu X, Wang C, Zhang X, Zhang R. LEF1 is associated with immunosuppressive microenvironment of patients with lung adenocarcinoma. Medicine (Baltimore) 2024; 103:e39892. [PMID: 39465830 PMCID: PMC11479531 DOI: 10.1097/md.0000000000039892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 09/11/2024] [Indexed: 10/29/2024] Open
Abstract
Wnt/β-Catenin pathway plays an important role in the occurrence and progression of malignant tumors, especially PD-L1-mediated tumor immune evasion. However, the role of TCF/LEF, an important member of the Wnt/β-catenin pathway, in the tumor immunosuppressive microenvironment of lung adenocarcinoma (LUAD) remains unknown. LUAD tissue-coding RNA expression data from The Cancer Genome Atlas and TIMER databases were used to analyze the expression of TCF/LEF transcription factors and their correlation with various immune cell infiltration. Immunohistochemistry and immunofluorescence were used to detect tissue protein staining in 105 patients with LUAD. LEF1, TCF7, TCF7L1 and TCF7L2 were all aberrantly expressed in the tumor tissues of LUAD patients with the data from The Cancer Genome Atlas (TCGA) database, tumor immune estimation resource (TIMER) database and results of immunohistochemistry, but only LEF1 expression was associated with 5-year overall survival in LUAD patients. LEF1 protein expression was associated with advanced tumor node metastasis (TNM) stage, lymphatic metastasis and local invasion in 105 cases LUAD patients. At the same time, LEF1 mRNA expression was also associated with immunosuppressive microenvironment in LUAD patients with the data from TCGA database and TIMER database. Results of immunohistochemistry and immunofluorescence in tumor tissues of 105 cases LUAD patients showed that there was a positively correlation between LEF1 protein expression and the infiltration of M2 macrophages and Treg cells. LEF1 was highly expressed in tumor tissues of LUAD patients, and highly expressed LEF1 was associated with the immunosuppressive microenvironment of LUAD patients.
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Affiliation(s)
- Xiaoqing Liu
- Department of Pathology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Chunlou Wang
- Department of Pathology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Xiaoling Zhang
- Department of Pathology, Cangzhou Central Hospital, Cangzhou, Hebei, China
| | - Rongju Zhang
- Department of Pathology, Cangzhou Central Hospital, Cangzhou, Hebei, China
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22
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Hu T, Liu CH, Lei M, Zeng Q, Li L, Tang H, Zhang N. Metabolic regulation of the immune system in health and diseases: mechanisms and interventions. Signal Transduct Target Ther 2024; 9:268. [PMID: 39379377 PMCID: PMC11461632 DOI: 10.1038/s41392-024-01954-6] [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: 03/27/2024] [Revised: 07/18/2024] [Accepted: 08/11/2024] [Indexed: 10/10/2024] Open
Abstract
Metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and other metabolic pathways, impacts the phenotypes and functions of immune cells. The metabolic regulation of the immune system is important in the pathogenesis and progression of numerous diseases, such as cancers, autoimmune diseases and metabolic diseases. The concept of immunometabolism was introduced over a decade ago to elucidate the intricate interplay between metabolism and immunity. The definition of immunometabolism has expanded from chronic low-grade inflammation in metabolic diseases to metabolic reprogramming of immune cells in various diseases. With immunometabolism being proposed and developed, the metabolic regulation of the immune system can be gradually summarized and becomes more and more clearer. In the context of many diseases including cancer, autoimmune diseases, metabolic diseases, and many other disease, metabolic reprogramming occurs in immune cells inducing proinflammatory or anti-inflammatory effects. The phenotypic and functional changes of immune cells caused by metabolic regulation further affect and development of diseases. Based on experimental results, targeting cellular metabolism of immune cells becomes a promising therapy. In this review, we focus on immune cells to introduce their metabolic pathways and metabolic reprogramming, and summarize how these metabolic pathways affect immune effects in the context of diseases. We thoroughly explore targets and treatments based on immunometabolism in existing studies. The challenges of translating experimental results into clinical applications in the field of immunometabolism are also summarized. We believe that a better understanding of immune regulation in health and diseases will improve the management of most diseases.
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Affiliation(s)
- Tengyue Hu
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Chang-Hai Liu
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Min Lei
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China
- National Center for Birth Defect Monitoring, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Qingmin Zeng
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Li Li
- Division of Renal and endocrinology, Qin Huang Hospital, Xi'an, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, China.
- Laboratory of Infectious and Liver Diseases, Institution of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China.
| | - Nannan Zhang
- West China School of clinical medical, West China Second University Hospital, Sichuan University, Chengdu, China.
- National Center for Birth Defect Monitoring, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China.
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China.
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23
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Huang T, Lian D, Chen M, Liu Y, Zhang M, Zeng D, Zhou SK, Ying W. Prognostic value of a lactate metabolism gene signature in lung adenocarcinoma and its associations with immune checkpoint blockade therapy response. Medicine (Baltimore) 2024; 103:e39371. [PMID: 39465750 PMCID: PMC11460856 DOI: 10.1097/md.0000000000039371] [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: 03/23/2023] [Indexed: 10/29/2024] Open
Abstract
Lung adenocarcinoma (LUAD) is a study that examines the prognostic value of lactate metabolism genes in tumor cells, which are associated with clinical prognosis. We analyzed the expression and clinical data for LUAD from The Cancer Genome Atlas database, using the GSE68465 dataset from the Gene Expression Omnibus and the MSigDB database. LASSO Cox regression and stepwise Cox regression were used to identify the optimal lactate metabolism gene signature. Differences in immune infiltration, tumor mutation burden (TMB), and response to immune checkpoint blockade (ICB) therapy were evaluated between groups. LASSO and Cox regression analyses showed an eight-lactate metabolism gene signature for model construction in both TCGA cohort and GSE68465 data, with higher survival outcomes in high-risk groups. The lactate metabolism risk score had an independent prognostic value (hazard ratio: 2.279 [1.652-3.146], P < .001). Immune cell infiltration differed between the risk groups, such as CD8+ T cells, macrophages, dendritic cells, mast cells, and neutrophils. The high-risk group had higher tumor purity, lower immune and stromal scores, and higher TMB. High-risk samples had high tumor immune dysfunction and exclusion (TIDE) scores and low cytolytic activity (CYT) scores, indicating a poor response to ICB therapy. Similarly, most immune checkpoint molecules, immune inhibitors/stimulators, and major histocompatibility complex (MHC) molecules were highly expressed in the high-risk group. The 8-lactate metabolism gene-based prognostic model predicts patient survival, immune infiltration, and ICB response in patients with LUAD, driving the development of therapeutic strategies to target lactate metabolism.
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Affiliation(s)
- Tengfei Huang
- Department of Thoracic and Cardiac Surgery, The 900th Hospital of the Joint Logistics Support Force of the People’s Liberation Army, Fuzhou, Fujian Province, China
| | - DuoHuang Lian
- Department of Thoracic and Cardiac Surgery, The 900th Hospital of the Joint Logistics Support Force of the People’s Liberation Army, Fuzhou, Fujian Province, China
| | - MengMeng Chen
- Department of Thoracic and Cardiac Surgery, The 900th Hospital of the Joint Logistics Support Force of the People’s Liberation Army, Fuzhou, Fujian Province, China
| | - YaMing Liu
- Department of Thoracic and Cardiac Surgery, The 900th Hospital of the Joint Logistics Support Force of the People’s Liberation Army, Fuzhou, Fujian Province, China
| | - MeiQing Zhang
- Department of Thoracic and Cardiac Surgery, The 900th Hospital of the Joint Logistics Support Force of the People’s Liberation Army, Fuzhou, Fujian Province, China
| | - DeHua Zeng
- Department of Thoracic and Cardiac Surgery, The 900th Hospital of the Joint Logistics Support Force of the People’s Liberation Army, Fuzhou, Fujian Province, China
| | - Shun-Kai Zhou
- Department of Thoracic and Cardiac Surgery, The 900th Hospital of the Joint Logistics Support Force of the People’s Liberation Army, Fuzhou, Fujian Province, China
| | - WenMin Ying
- Department of Radiotherapy, Fuding Hospital, Fuding, Fujian Province, China
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24
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Lv W, Wang Y. Neural Influences on Tumor Progression Within the Central Nervous System. CNS Neurosci Ther 2024; 30:e70097. [PMID: 39469896 PMCID: PMC11519750 DOI: 10.1111/cns.70097] [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: 07/08/2024] [Revised: 09/21/2024] [Accepted: 10/13/2024] [Indexed: 10/30/2024] Open
Abstract
For decades, researchers have studied how brain tumors, the immune system, and drugs interact. With the advances in cancer neuroscience, which centers on defining and therapeutically targeting nervous system-cancer interactions, both within the local tumor microenvironment (TME) and on a systemic level, the subtle relationship between neurons and tumors in the central nervous system (CNS) has been deeply studied. Neurons, as the executors of brain functional activities, have been shown to significantly influence the emergence and development of brain tumors, including both primary and metastatic tumors. They engage with tumor cells via chemical or electrical synapses, directly regulating tumors or via intricate coupling networks, and also contribute to the TME through paracrine signaling, secreting proteins that exert regulatory effects. For instance, in a study involving a mouse model of glioblastoma, the authors observed a 42% increase in tumor volume when neuronal activity was stimulated, compared to controls (p < 0.01), indicating a direct correlation between neural activity and tumor growth. These thought-provoking results offer promising new strategies for brain tumor therapies, highlighting the potential of neuronal modulation to curb tumor progression. Future strategies may focus on developing drugs to inhibit or neutralize proteins and other bioactive substances secreted by neurons, break synaptic connections and interactions between infiltrating cells and tumor cells, as well as disrupt electrical coupling within glioma cell networks. By harnessing the insights gained from this research, we aspire to usher in a new era of brain tumor therapies that are both more potent and precise.
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Affiliation(s)
- Wenhao Lv
- Affiliated Hospital of Hangzhou Normal UniversityHangzhou Normal UniversityHangzhouZhejiangChina
- School of PharmacyHangzhou Normal UniversityHangzhouZhejiangChina
| | - Yongjie Wang
- School of PharmacyHangzhou Normal UniversityHangzhouZhejiangChina
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25
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Gaebler D, Hachey SJ, Hughes CCW. Improving tumor microenvironment assessment in chip systems through next-generation technology integration. Front Bioeng Biotechnol 2024; 12:1462293. [PMID: 39386043 PMCID: PMC11461320 DOI: 10.3389/fbioe.2024.1462293] [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: 07/09/2024] [Accepted: 09/10/2024] [Indexed: 10/12/2024] Open
Abstract
The tumor microenvironment (TME) comprises a diverse array of cells, both cancerous and non-cancerous, including stromal cells and immune cells. Complex interactions among these cells play a central role in driving cancer progression, impacting critical aspects such as tumor initiation, growth, invasion, response to therapy, and the development of drug resistance. While targeting the TME has emerged as a promising therapeutic strategy, there is a critical need for innovative approaches that accurately replicate its complex cellular and non-cellular interactions; the goal being to develop targeted, personalized therapies that can effectively elicit anti-cancer responses in patients. Microfluidic systems present notable advantages over conventional in vitro 2D co-culture models and in vivo animal models, as they more accurately mimic crucial features of the TME and enable precise, controlled examination of the dynamic interactions among multiple human cell types at any time point. Combining these models with next-generation technologies, such as bioprinting, single cell sequencing and real-time biosensing, is a crucial next step in the advancement of microfluidic models. This review aims to emphasize the importance of this integrated approach to further our understanding of the TME by showcasing current microfluidic model systems that integrate next-generation technologies to dissect cellular intra-tumoral interactions across different tumor types. Carefully unraveling the complexity of the TME by leveraging next generation technologies will be pivotal for developing targeted therapies that can effectively enhance robust anti-tumoral responses in patients and address the limitations of current treatment modalities.
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Affiliation(s)
- Daniela Gaebler
- Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, United States
| | - Stephanie J. Hachey
- Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, United States
| | - Christopher C. W. Hughes
- Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, United States
- Biomedical Engineering, University of California, Irvine, Irvine, CA, United States
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26
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Jiang R, Ren WJ, Wang LY, Zhang W, Jiang ZH, Zhu GY. Targeting Lactate: An Emerging Strategy for Macrophage Regulation in Chronic Inflammation and Cancer. Biomolecules 2024; 14:1202. [PMID: 39456135 PMCID: PMC11505598 DOI: 10.3390/biom14101202] [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: 08/27/2024] [Revised: 09/16/2024] [Accepted: 09/20/2024] [Indexed: 10/28/2024] Open
Abstract
Lactate accumulation and macrophage infiltration are pivotal features of both chronic inflammation and cancer. Lactate, once regarded merely as an aftereffect of glucose metabolism, is now gaining recognition for its burgeoning spectrum of biological roles and immunomodulatory significance. Recent studies have evidenced that macrophages display divergent immunophenotypes in different diseases, which play a pivotal role in disease management by modulating macrophage polarization within the disease microenvironment. The specific polarization patterns of macrophages in a high-lactate environment and their contribution to the progression of chronic inflammation and cancer remain contentious. This review presents current evidence on the crosstalk of lactate and macrophage in chronic inflammation and cancer. Additionally, we provide an in-depth exploration of the pivotal yet enigmatic mechanisms through which lactate orchestrates disease pathogenesis, thereby offering novel perspectives to the development of targeted therapeutic interventions for chronic inflammation and cancer.
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Affiliation(s)
| | | | | | | | - Zhi-Hong Jiang
- State Key Laboratory of Quality Research in Chinese Medicine, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, Macau Institute for Applied Research in Medicine and Health, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (R.J.); (W.-J.R.); (L.-Y.W.); (W.Z.)
| | - Guo-Yuan Zhu
- State Key Laboratory of Quality Research in Chinese Medicine, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, Macau Institute for Applied Research in Medicine and Health, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (R.J.); (W.-J.R.); (L.-Y.W.); (W.Z.)
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27
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Zhang Y, Ding X, Zhang X, Li Y, Xu R, Li HJ, Zuo D, Chen G. Unveiling the contribution of tumor-associated macrophages in driving epithelial-mesenchymal transition: a review of mechanisms and therapeutic Strategies. Front Pharmacol 2024; 15:1404687. [PMID: 39286635 PMCID: PMC11402718 DOI: 10.3389/fphar.2024.1404687] [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: 03/21/2024] [Accepted: 08/15/2024] [Indexed: 09/19/2024] Open
Abstract
Tumor-associated macrophages (TAMs), fundamental constituents of the tumor microenvironment (TME), significantly influence cancer development, primarily by promoting epithelial-mesenchymal transition (EMT). EMT endows cancer cells with increased motility, invasiveness, and resistance to therapies, marking a pivotal juncture in cancer progression. The review begins with a detailed exposition on the origins of TAMs and their functional heterogeneity, providing a foundational understanding of TAM characteristics. Next, it delves into the specific molecular mechanisms through which TAMs induce EMT, including cytokines, chemokines and stromal cross-talking. Following this, the review explores TAM-induced EMT features in select cancer types with notable EMT characteristics, highlighting recent insights and the impact of TAMs on cancer progression. Finally, the review concludes with a discussion of potential therapeutic targets and strategies aimed at mitigating TAM infiltration and disrupting the EMT signaling network, thereby underscoring the potential of emerging treatments to combat TAM-mediated EMT in cancer. This comprehensive analysis reaffirms the necessity for continued exploration into TAMs' regulatory roles within cancer biology to refine therapeutic approaches and improve patient outcomes.
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Affiliation(s)
- Yijia Zhang
- Department of Pharmacy, Taizhou Second People's Hospital (Mental Health Center affiliated to Taizhou University School of Medicine), Taizhou University, Taizhou, Zhejiang, China
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Xiaofei Ding
- Department of Pharmacology, Taizhou University, Taizhou, Zhejiang, China
| | - Xue Zhang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Ye Li
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Rui Xu
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Hai-Jun Li
- Department of Pharmacy, Taizhou Second People's Hospital (Mental Health Center affiliated to Taizhou University School of Medicine), Taizhou University, Taizhou, Zhejiang, China
| | - Daiying Zuo
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Guang Chen
- Department of Pharmacy, Taizhou Second People's Hospital (Mental Health Center affiliated to Taizhou University School of Medicine), Taizhou University, Taizhou, Zhejiang, China
- Department of Pharmacology, Taizhou University, Taizhou, Zhejiang, China
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28
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Du H, Sun J, Wang X, Zhao L, Liu X, Zhang C, Wang F, Wu J. FOSL2-mediated transcription of ISG20 induces M2 polarization of macrophages and enhances tumorigenic ability of glioblastoma cells. J Neurooncol 2024; 169:659-670. [PMID: 39073688 DOI: 10.1007/s11060-024-04771-7] [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: 03/13/2024] [Accepted: 07/05/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Interferon stimulated exonuclease gene 20 (ISG20) has been reported to be correlated with macrophage infiltration in glioblastoma (GBM) in previous bioinformatics-based studies. This study explores the exact effect of ISG20 on macrophage polarization in GBM. METHODS ISG20 expression in GBM tissues and cells was determined by RT-qPCR and/or immunohistochemistry. GBM cells were co-cultured with M0 macrophages (PMA-stimulated THP-1 cells) in vitro, followed by flow cytometry and ELISA to analyze the M2 polarization of macrophages. Fluorescence-contained GBM cells were intracranially injected into nude mice along with M0 macrophages to generate orthotopic xenograft tumor models. Upstream regulator of ISG20 was predicted using bioinformatics. Loss- or gain-of-function assays of Fos like 2 (FOSL2) and ISG20 were performed in GBM cells. DNA methylation level of FOSL2 was analyzed by bisulfite sequencing analysis. RESULTS ISG20 was found highly expressed in GBM tissues and cells. ISG20 silencing in GBM cells decreased CD206 and CD163 levels in the co-cultured macrophages and reduced secretion of IL-10 and TGF-β. It also enhanced survival of nude mice bearing xenograft tumors, blocked tumor growth, and suppressed M2 polarization of macrophages in vivo. FOSL2, highly expressed in GBM, bound to the ISG20 promoter to activate its transcription. FOSL2 silencing similarly blocked M2 polarization of macrophages, which was negated by ISG20 overexpression. The high FOSL2 expression in GBM was attributed to DNA hypomethylation. CONCLUSION This study demonstrates that FOSL2 is highly expressed in GBM due to DNA hypomethylation. It activates transcription of ISG20, thus promoting M2 polarization of macrophages and GBM development.
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Affiliation(s)
- Hailong Du
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Shijiazhuang, 050000, Hebei, P.R. China
| | - Jianping Sun
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Shijiazhuang, 050000, Hebei, P.R. China
| | - Xiaoliang Wang
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Shijiazhuang, 050000, Hebei, P.R. China
| | - Lei Zhao
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Shijiazhuang, 050000, Hebei, P.R. China
| | - Xiaosong Liu
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Shijiazhuang, 050000, Hebei, P.R. China
| | - Chao Zhang
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Shijiazhuang, 050000, Hebei, P.R. China
| | - Feng Wang
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Shijiazhuang, 050000, Hebei, P.R. China
| | - Jianliang Wu
- Department of Neurosurgery, The Second Hospital of Hebei Medical University, No. 215, Heping West Road, Shijiazhuang, 050000, Hebei, P.R. China.
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29
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Zhang F, Guo J, Yu S, Zheng Y, Duan M, Zhao L, Wang Y, Yang Z, Jiang X. Cellular senescence and metabolic reprogramming: Unraveling the intricate crosstalk in the immunosuppressive tumor microenvironment. Cancer Commun (Lond) 2024; 44:929-966. [PMID: 38997794 PMCID: PMC11492308 DOI: 10.1002/cac2.12591] [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: 11/26/2023] [Revised: 06/23/2024] [Accepted: 07/07/2024] [Indexed: 07/14/2024] Open
Abstract
The intrinsic oncogenic mechanisms and properties of the tumor microenvironment (TME) have been extensively investigated. Primary features of the TME include metabolic reprogramming, hypoxia, chronic inflammation, and tumor immunosuppression. Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME. Specifically, hypoxic adaptation, metabolic dysregulation, and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation, thereby promoting the progression of tumor events. This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME, with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells. The available findings suggest that components of the TME collectively contribute to the progression of tumor events. The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.
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Affiliation(s)
- Fusheng Zhang
- Department of General SurgeryThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
- Department of Hepatobiliary and Pancreatic SurgeryPeking University First HospitalBeijingP. R. China
| | - Junchen Guo
- Department of RadiologyThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Shengmiao Yu
- Outpatient DepartmentThe Fourth Affiliated HospitalChina Medical UniversityShenyangLiaoningP. R. China
| | - Youwei Zheng
- Department of General SurgeryThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Meiqi Duan
- Department of General SurgeryThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Liang Zhao
- Department of General SurgeryThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Yihan Wang
- Department of General SurgeryThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Zhi Yang
- Department of General SurgeryThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Xiaofeng Jiang
- Department of General SurgeryThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningP. R. China
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30
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Ding Z, Chen J, Li B, Ji X. Inflammatory factors and risk of lung adenocarcinoma: a Mendelian randomization study mediated by blood metabolites. Front Endocrinol (Lausanne) 2024; 15:1446863. [PMID: 39257908 PMCID: PMC11384989 DOI: 10.3389/fendo.2024.1446863] [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: 06/10/2024] [Accepted: 07/29/2024] [Indexed: 09/12/2024] Open
Abstract
Background Lung adenocarcinoma (LUAD) is the most common type of lung cancer, and its pathogenesis remains not fully elucidated. Inflammation and metabolic dysregulation are considered to play crucial roles in LUAD development, but their causal relationships and specific mechanisms remain unclear. Methods This study employed a two-sample Mendelian randomization (MR) approach to systematically evaluate the causal associations between 91 circulating inflammatory factors, 1,400 serum metabolites, and LUAD. We utilized LUAD genome-wide association studies (GWAS) data from the FinnGen biobank and GWAS data of metabolites and inflammatory factors from the GWAS catalog to conduct two-sample MR analyses. For the identified key metabolites, we further used mediator MR to investigate their mediating effects in the influence of IL-17A on LUAD and explored potential mechanisms through protein-protein interaction and functional enrichment analyses. Results The MR analyses revealed that IL-17A (OR 0.78, 95%CI 0.62-0.99) was negatively associated with LUAD, while 71 metabolites were significantly associated with LUAD. Among them, ferulic acid 4-sulfate may play a crucial mediating role in the suppression of LUAD by IL-17A (OR 0.87, 95%CI 0.78-0.97). IL-17A may exert its anti-LUAD effects through extensive interactions with genes related to ferulic acid 4-sulfate metabolism (such as SULT1A1, CYP1A1, etc.), inhibiting oxidative stress and inflammatory responses, as well as downstream tumor-related pathways of ferulic acid 4-sulfate (such as MAPK, NF-κB, etc.). Conclusion This study discovered causal associations between IL-17A, multiple serum metabolites, and LUAD occurrence, revealing the key role of inflammatory and metabolic dysregulation in LUAD pathogenesis. Our findings provide new evidence-based medical support for specific inflammatory factors and metabolites as early predictive and risk assessment biomarkers for LUAD, offering important clues for subsequent mechanistic studies and precision medicine applications.
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Affiliation(s)
- Zheng Ding
- Department of Cardiac Surgery, The First Affiliated Hospital of China Medical University, Liaoning, Shenyang, China
| | - Juan Chen
- Department of Medical Oncology, The First Affiliated Hospital of China Medical University, Liaoning, Shenyang, China
| | - Bohan Li
- Department of Urinary Surgery, The First Affiliated Hospital of China Medical University, Liaoning, Shenyang, China
| | - Xinyu Ji
- Department of Thoracic Surgery, The First Affiliated Hospital of China Medical University, Liaoning, Shenyang, China
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31
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Chen W, Chen M, Hong L, Xiahenazi A, Huang M, Tang N, Yang X, She F, Chen Y. M2-like tumor-associated macrophage-secreted CCL2 facilitates gallbladder cancer stemness and metastasis. Exp Hematol Oncol 2024; 13:83. [PMID: 39138521 PMCID: PMC11320879 DOI: 10.1186/s40164-024-00550-2] [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: 02/01/2024] [Accepted: 07/30/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND The predominant immune cells in solid tumors are M2-like tumor-associated macrophages (M2-like TAMs), which significantly impact the promotion of epithelial-mesenchymal transition (EMT) in tumors, enhancing stemness and facilitating tumor invasion and metastasis. However, the contribution of M2-like TAMs to tumor progression in gallbladder cancer (GBC) is partially known. METHODS Immunohistochemistry was used to evaluate the expression of M2-like TAMs and cancer stem cell (CSC) markers in 24 pairs of GBC and adjacent noncancerous tissues from patients with GBC. Subsequently, GBC cells and M2-like TAMs were co-cultured to examine the expression of CSC markers, EMT markers, and migratory behavior. Proteomics was performed on the culture supernatant of M2-like TAMs. The mechanisms underlying the induction of EMT, stemness, and metastasis in GBC by M2-like TAMs were elucidated using proteomics and transcriptomics. GBC cells were co-cultured with undifferentiated macrophages (M0) and analyzed. The therapeutic effect of gemcitabine combined with a chemokine (C-C motif) receptor 2 (CCR2) antagonist on GBC was observed in vivo. RESULTS The expression levels of CD68 and CD163 in M2-like TAMs and CD44 and CD133 in gallbladder cancer stem cells (GBCSCs) were increased and positively correlated in GBC tissues compared with those in neighboring noncancerous tissues. M2-like TAMs secreted a significant amount of chemotactic cytokine ligand 2 (CCL2), which activated the MEK/extracellular regulated protein kinase (ERK) pathway and enhanced SNAIL expression after binding to the receptor CCR2 on GBC cells. Activation of the ERK pathway caused nuclear translocation of ELK1, which subsequently led to increased SNAIL expression. GBCSCs mediated the recruitment and polarization of M0 into M2-like TAMs within the GBC microenvironment via CCL2 secretion. In the murine models, the combination of a CCR2 antagonist and gemcitabine efficiently inhibited the growth of subcutaneous tumors in GBC. CONCLUSIONS The interaction between M2-like TAMs and GBC cells is mediated by the chemokine CCL2, which activates the MEK/ERK/ELK1/SNAIL pathway in GBC cells, promoting EMT, stemness, and metastasis. A combination of a CCR2 inhibitor and gemcitabine effectively suppressed the growth of subcutaneous tumors. Consequently, our study identified promising therapeutic targets and strategies for treating GBC.
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Affiliation(s)
- Weihong Chen
- Department of Hepatobiliary Surgery, Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China
- Fujian Medical University Cancer Center, Fuzhou, 350108, China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350108, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, 350108, Fujian, China
| | - Mingyuan Chen
- Department of Hepatobiliary Surgery, Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China
- Fujian Medical University Cancer Center, Fuzhou, 350108, China
| | - Lingju Hong
- Department of Hepatobiliary Surgery, Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China
| | - Abudukeremu Xiahenazi
- Department of Hepatobiliary Surgery, Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China
- Fujian Medical University Cancer Center, Fuzhou, 350108, China
| | - Maotuan Huang
- Department of Hepatobiliary Surgery, Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China
- Fujian Medical University Cancer Center, Fuzhou, 350108, China
| | - Nanhong Tang
- Department of Hepatobiliary Surgery, Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China
- Fujian Medical University Cancer Center, Fuzhou, 350108, China
| | - Xinyue Yang
- Department of Hepatobiliary Surgery, Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China
- Fujian Medical University Cancer Center, Fuzhou, 350108, China
| | - Feifei She
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350108, China.
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, 350108, Fujian, China.
| | - Yanling Chen
- Department of Hepatobiliary Surgery, Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China.
- Fujian Medical University Cancer Center, Fuzhou, 350108, China.
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350108, China.
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Liu Y, Zhao Y, Song H, Li Y, Liu Z, Ye Z, Zhao J, Wu Y, Tang J, Yao M. Metabolic reprogramming in tumor immune microenvironment: Impact on immune cell function and therapeutic implications. Cancer Lett 2024; 597:217076. [PMID: 38906524 DOI: 10.1016/j.canlet.2024.217076] [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: 03/18/2024] [Revised: 05/23/2024] [Accepted: 06/17/2024] [Indexed: 06/23/2024]
Abstract
Understanding of the metabolic reprogramming has revolutionized our insights into tumor progression and potential treatment. This review concentrates on the aberrant metabolic pathways in cancer cells within the tumor microenvironment (TME). Cancer cells differ from normal cells in their metabolic processing of glucose, amino acids, and lipids in order to adapt to heightened biosynthetic and energy needs. These metabolic shifts, which crucially alter lactic acid, amino acid and lipid metabolism, affect not only tumor cell proliferation but also TME dynamics. This review also explores the reprogramming of various immune cells in the TME. From a therapeutic standpoint, targeting these metabolic alterations represents a novel cancer treatment strategy. This review also discusses approaches targeting the regulation of metabolism of different nutrients in tumor cells and influencing the tumor microenvironment to enhance the immune response. In summary, this review summarizes metabolic reprogramming in cancer and its potential as a target for innovative therapeutic strategies, offering fresh perspectives on cancer treatment.
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Affiliation(s)
- Yuqiang Liu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Thoracic Surgery and Oncology, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510182, China
| | - Yu Zhao
- Department of Thoracic Surgery, Sheng Jing Hospital, China Medical University, Shenyang, Liaoning, 110000, China
| | - Huisheng Song
- Affiliated Qingyuan Hospital, Guangzhou Medica University, Qingyuan People's Hospital, Qingyuan, Guangdong, 511500, China
| | - Yunting Li
- Department of Pediatrics, Guangzhou Medical University, Guangzhou, Guangdong, 510182, China
| | - Zihao Liu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Thoracic Surgery and Oncology, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510182, China
| | - Zhiming Ye
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Thoracic Surgery and Oncology, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510182, China
| | - Jianzhu Zhao
- Department of oncology, Sheng Jing Hospital, China Medical University, Shenyang, Liaoning, 110000, China
| | - Yuzheng Wu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Thoracic Surgery and Oncology, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510182, China
| | - Jun Tang
- Department of Thoracic Surgery, Sheng Jing Hospital, China Medical University, Shenyang, Liaoning, 110000, China.
| | - Maojin Yao
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Department of Thoracic Surgery and Oncology, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510182, China.
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Ren B, Li X, Zhang Z, Tai S, Yu S. Exosomes: a significant medium for regulating drug resistance through cargo delivery. Front Mol Biosci 2024; 11:1379822. [PMID: 39135913 PMCID: PMC11317298 DOI: 10.3389/fmolb.2024.1379822] [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: 01/31/2024] [Accepted: 06/17/2024] [Indexed: 08/15/2024] Open
Abstract
Exosomes are small lipid nanovesicles with a diameter of 30-150 nm. They are present in all body fluids and are actively secreted by the majority of cells through the process of exocytosis. Exosomes play an essential role in intercellular communication and act as significant molecular carriers in regulating various physiological and pathological processes, such as the emergence of drug resistance in tumors. Tumor-associated exosomes transfer drug resistance to other tumor cells by releasing substances such as multidrug resistance proteins and miRNAs through exosomes. These substances change the cell phenotype, making it resistant to drugs. Tumor-associated exosomes also play a role in impacting drug resistance in other cells, like immune cells and stromal cells. Exosomes alter the behavior and function of these cells to help tumor cells evade immune surveillance and form a tumor niche. In addition, exosomes also export substances such as tumoricidal drugs and neutralizing antibody drugs to help tumor cells resist drug therapy. In this review, we summarize the mechanisms of exosomes in promoting drug resistance by delivering cargo in the context of the tumor microenvironment (TME).
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Affiliation(s)
- Bixuan Ren
- Department of Hepatic Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaoqing Li
- Department of Pathology, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhihua Zhang
- Department of Hepatic Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Sheng Tai
- Department of Hepatic Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shan Yu
- Department of Pathology, Second Affiliated Hospital of Harbin Medical University, Harbin, China
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Chen G, Lin L, Mai Z, Tang Y, Zhang Q, Chen G, Li Z, Zhang J, Wang Y, Yang Y, Yu Z. Carrier-Free Photodynamic Bioregulators Inhibiting Lactic Acid Efflux Combined with Immune Checkpoint Blockade for Triple-Negative Breast Cancer Immunotherapy. ACS NANO 2024. [PMID: 39034461 DOI: 10.1021/acsnano.4c07213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/23/2024]
Abstract
Abnormal tumor metabolism creates a complex tumor immune microenvironment that plays a dominant role in the metastasis of triple-negative breast cancer (TNBC). TNBC is insensitive to immune checkpoint blockade (ICB) therapy because of insufficient cytotoxic T lymphocyte (CTL) infiltration and a hyper-lactic acid-suppressive immune microenvironment caused by abnormal glycolysis. Herein, we propose an amplified strategy based on lactic acid regulation to reprogram the immunosuppressive tumor microenvironment (ITM) and combine it with ICB therapy to achieve enhanced antitumor immunotherapy effects. Specifically, we constructed CASN, a carrier-free photodynamic bioregulator, through the self-assembly of the photosensitizer Chlorin e6 and monocarboxylate transporter 1 (MCT1) inhibitor AZD3965. CASN exhibited a uniform structure, good stability, and drug accumulation at the tumor site. CASN-mediated photodynamic therapy following laser irradiation inhibited primary tumor growth and induced immunogenic cell death. Furthermore, CASN reduced lactic acid-mediated regulatory T cell generation and M2 tumor-associated macrophage polarization by blocking MCT1-mediated lactic acid efflux to attenuate immune suppression, inducing the recruitment and activation of CTLs. Ultimately, CASN-mediated immunopotentiation combined with ICB therapy considerably strengthened tumor immunotherapy and effectively inhibited tumor growth and metastasis of TNBC. This synergistic amplification strategy overcomes the limitations of an acidic ITM and presents a potential clinical treatment option for metastatic tumors.
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Affiliation(s)
- Guimei Chen
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Ling Lin
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Ziyi Mai
- Department of Pharmacy, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China
| | - Yan Tang
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Qiaoling Zhang
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Gui Chen
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Zibo Li
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jiasi Zhang
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
| | - Yongxia Wang
- Department of Galactophore, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Dongguan 523058, China
| | - Yuanyuan Yang
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
| | - Zhiqiang Yu
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
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Sun J, Feng Q, He Y, Wang M, Wu Y. Lactate activates CCL18 expression via H3K18 lactylation in macrophages to promote tumorigenesis of ovarian cancer. Acta Biochim Biophys Sin (Shanghai) 2024; 56:1373-1386. [PMID: 39010846 PMCID: PMC11543520 DOI: 10.3724/abbs.2024111] [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: 09/10/2023] [Accepted: 02/02/2024] [Indexed: 07/17/2024] Open
Abstract
This study investigates the role of lactate in the genesis and progression of ovarian cancer (OV) and explores the underlying mechanisms. Serum lactate levels show a positive correlation with tumor grade and poor prognosis in patients with OV. Bioinformatics analysis identifies CCL18 as a lactate-related gene in OV. CCL18 is up-regulated in cancerous tissues and positively related to serum lactate levels in OV patients. THP-1 cells are exposed to phorbol-12-myristate-13-acetate for M0 macrophage induction. The results of RT-qPCR and ELISA for M1/M2 macrophage-related markers and inflammatory cytokines show that the exposure of lactate to macrophages induces M2 polarization. Based on the coculture of OV cells with macrophages, lactate-treated macrophages induces a significant increase in the proliferation and migration of OV cells. However, these effects can be reversed by silencing of Gpr132 in macrophages or treatment with anti-CCL18 antibody. Experiments using the xenograft model verify that the oncogenic role of lactate in tumor growth and metastasis relies on Gpr132 and CCL18. ChIP-qPCR and luciferase reporter assays reveal that lactate regulates CCL18 expression via H3K18 lactylation. In conclusion, lactate is a potential therapeutic target for OV. It is involved in tumorigenesis by activating CCL18 expression via H3K18 lactylation in macrophages.
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Affiliation(s)
- Jinrui Sun
- Department of GynecologyShanxi Provincial People’s HospitalTaiyuan030001China
- Department of Gynecologic OncologyBeijing Obstetrics and Gynecology HospitalCapital Medical UniversityBeijing Maternal and Child Health Care HospitalBeijing100006China
| | - Qinmei Feng
- Department of GynecologyShanxi Provincial People’s HospitalTaiyuan030001China
| | - Yue He
- Department of Gynecologic OncologyBeijing Obstetrics and Gynecology HospitalCapital Medical UniversityBeijing Maternal and Child Health Care HospitalBeijing100006China
| | - Ming Wang
- Department of Gynecologic OncologyBeijing Obstetrics and Gynecology HospitalCapital Medical UniversityBeijing Maternal and Child Health Care HospitalBeijing100006China
| | - Yumei Wu
- Department of Gynecologic OncologyBeijing Obstetrics and Gynecology HospitalCapital Medical UniversityBeijing Maternal and Child Health Care HospitalBeijing100006China
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Guo X, Yang Y, Qian Z, Chang M, Zhao Y, Ma W, Wang Y, Xing B. Immune landscape and progress in immunotherapy for pituitary neuroendocrine tumors. Cancer Lett 2024; 592:216908. [PMID: 38677640 DOI: 10.1016/j.canlet.2024.216908] [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: 02/07/2024] [Revised: 04/17/2024] [Accepted: 04/18/2024] [Indexed: 04/29/2024]
Abstract
Pituitary neuroendocrine tumors (pitNETs) are the second most common primary brain tumors. Despite their prevalence, the tumor immune microenvironment (TIME) and its clinical implications remain largely unexplored. This review provides a comprehensive overview of current knowledge on the immune landscape and advancements in targeted immunotherapy for pitNETs. Macrophages and T cells are principal immune infiltrates within the TIME. Different subtypes of pitNETs display distinct immune patterns, influencing tumor progressive behaviors. PD-L1, the most extensively studied immune checkpoint, is prominently expressed in hormonal pitNETs and correlates with tumor growth and invasion. Cytokines and chemokines including interleukins, CCLs, and CXCLs have complex correlations with tumor subtypes and immune cell infiltration. Crosstalk between macrophages and pitNET cells highlights bidirectional regulatory roles, suggesting potential macrophage-targeted strategies. Recent preclinical studies have demonstrated the efficacy of anti-PD-L1 therapy in a mouse model of corticotroph pitNET. Moreover, anti-PD-1 and/or anti-CTLA-4 immunotherapy has been applied globally in 28 cases of refractory pitNETs, showing more favorable responses in pituitary carcinomas than aggressive pitNETs. In conclusion, the TIME of pitNETs represents a promising avenue for targeted immunotherapy and warrants further investigation.
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Affiliation(s)
- Xiaopeng Guo
- Department of Neurosurgery, Key Laboratory of Endocrinology of National Ministry of Health, China Pituitary Adenoma Specialist Council, China Pituitary Disease Registry Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yiying Yang
- Department of Neurosurgery, Key Laboratory of Endocrinology of National Ministry of Health, China Pituitary Adenoma Specialist Council, China Pituitary Disease Registry Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Eight-Year Program of Clinical Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China
| | - Zhihong Qian
- Department of Neurosurgery, Key Laboratory of Endocrinology of National Ministry of Health, China Pituitary Adenoma Specialist Council, China Pituitary Disease Registry Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
| | - Mengqi Chang
- Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuanli Zhao
- Department of Neurosurgery, Key Laboratory of Endocrinology of National Ministry of Health, China Pituitary Adenoma Specialist Council, China Pituitary Disease Registry Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenbin Ma
- Department of Neurosurgery, Key Laboratory of Endocrinology of National Ministry of Health, China Pituitary Adenoma Specialist Council, China Pituitary Disease Registry Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu Wang
- Department of Neurosurgery, Key Laboratory of Endocrinology of National Ministry of Health, China Pituitary Adenoma Specialist Council, China Pituitary Disease Registry Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Bing Xing
- Department of Neurosurgery, Key Laboratory of Endocrinology of National Ministry of Health, China Pituitary Adenoma Specialist Council, China Pituitary Disease Registry Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Wang Z, Ji X, Zhang Y, Yang F, Su H, Zhang H, Li Z, Zhang W, Sun W. Interactions between LAMP3+ dendritic cells and T-cell subpopulations promote immune evasion in papillary thyroid carcinoma. J Immunother Cancer 2024; 12:e008983. [PMID: 38816233 PMCID: PMC11141193 DOI: 10.1136/jitc-2024-008983] [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] [Accepted: 05/13/2024] [Indexed: 06/01/2024] Open
Abstract
BACKGROUND The incidence of papillary thyroid cancer (PTC) continues to rise all over the world, 10-15% of the patients have a poor prognosis. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains far from satisfactory, necessitating further investigation of the mechanism of PTC immune remodeling and exploration of novel treatment targets. METHODS This study conducted a single-cell RNA sequencing (scRNA-seq) analysis using 18 surgical tissue specimens procured from 14 patients diagnosed with adjacent tissues, non-progressive PTC or progressive PTC. Key findings were authenticated through spatial transcriptomics RNA sequencing, immunohistochemistry, multiplex immunohistochemistry, and an independent bulk RNA-seq data set containing 502 samples. RESULTS A total of 151,238 individual cells derived from 18 adjacent tissues, non-progressive PTC and progressive PTC specimens underwent scRNA-seq analysis. We found that progressive PTC exhibits the following characteristics: a significant decrease in overall immune cells, enhanced immune evasion of tumor cells, and disrupted antigen presentation function. Moreover, we identified a subpopulation of lysosomal associated membrane protein 3 (LAMP3+) dendritic cells (DCs) exhibiting heightened infiltration in progressive PTC and associated with advanced T stage and poor prognosis of PTC. LAMP3+ DCs promote CD8+ T cells exhaustion (mediated by NECTIN2-TIGIT) and increase infiltration abundance of regulatory T cells (mediated by chemokine (C-C motif) ligand 17 (CCL17)-chemokine (C-C motif) receptor 4 (CCR4)) establishing an immune-suppressive microenvironment. Ultimately, we unveiled that progressive PTC tumor cells facilitate the retention of LAMP3+ DCs within the tumor microenvironment through NECTIN3-NECTIN2 interactions, thereby rendering tumor cells more susceptible to immune evasion. CONCLUSION Our findings expound valuable insights into the role of the interaction between LAMP3+ DCs and T-cell subpopulations and offer new and effective ideas and strategies for immunotherapy in patients with progressive PTC.
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Affiliation(s)
- Zhiyuan Wang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Xiaoyu Ji
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Ye Zhang
- The First Laboratory of Cancer Institute, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Fan Yang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Hongyue Su
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Hao Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Zhendong Li
- Department of Head and Neck Surgery, Cancer Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Wenqian Zhang
- Department of Head and Neck Surgery, Cancer Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Wei Sun
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China
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Xu B, Liu Y, Li N, Geng Q. Lactate and lactylation in macrophage metabolic reprogramming: current progress and outstanding issues. Front Immunol 2024; 15:1395786. [PMID: 38835758 PMCID: PMC11148263 DOI: 10.3389/fimmu.2024.1395786] [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: 03/04/2024] [Accepted: 05/07/2024] [Indexed: 06/06/2024] Open
Abstract
It is commonly known that different macrophage phenotypes play specific roles in different pathophysiological processes. In recent years, many studies have linked the phenotypes of macrophages to their characteristics in different metabolic pathways, suggesting that macrophages can perform different functions through metabolic reprogramming. It is now gradually recognized that lactate, previously overlooked as a byproduct of glycolytic metabolism, acts as a signaling molecule in regulating multiple biological processes, including immunological responses and metabolism. Recently, lactate has been found to mediate epigenetic changes in macrophages through a newfound lactylation modification, thereby regulating their phenotypic transformation. This novel finding highlights the significant role of lactate metabolism in macrophage function. In this review, we summarize the features of relevant metabolic reprogramming in macrophages and the role of lactate metabolism therein. We also review the progress of research on the regulation of macrophage metabolic reprogramming by lactylation through epigenetic mechanisms.
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Affiliation(s)
- Bangjun Xu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yi Liu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ning Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
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Liu Y, Zhang X, Pang Z, Wang Y, Zheng H, Wang G, Wang K, Du J. Prediction of prognosis and immunotherapy efficacy based on metabolic landscape in lung adenocarcinoma by bulk, single-cell RNA sequencing and Mendelian randomization analyses. Aging (Albany NY) 2024; 16:8772-8809. [PMID: 38771130 PMCID: PMC11164486 DOI: 10.18632/aging.205838] [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: 10/24/2023] [Accepted: 04/16/2024] [Indexed: 05/22/2024]
Abstract
Immunotherapy has been a remarkable clinical advancement in cancer treatment, but only a few patients benefit from it. Metabolic reprogramming is tightly associated with immunotherapy efficacy and clinical outcomes. However, comprehensively analyzing their relationship is still lacking in lung adenocarcinoma (LUAD). Herein, we evaluated 84 metabolic pathways in TCGA-LUAD by ssGSEA. A matrix of metabolic pathway pairs was generated and a metabolic pathway-pair score (MPPS) model was established by univariable, LASSO, multivariable Cox regression analyses. The differences of metabolic reprogramming, tumor microenvironment (TME), tumor mutation burden and drug sensitivity in different MPPS groups were further explored. WGCNA and 117 machine learning algorithms were performed to identify MPPS-related genes. Single-cell RNA sequencing and in vitro experiments were used to explore the role of C1QTNF6 on TME. The results showed MPPS model accurately predicted prognosis and immunotherapy efficacy of LUAD patients regardless of sequencing platforms. High-MPPS group had worse prognosis, immunotherapy efficacy and lower immune cells infiltration, immune-related genes expression and cancer-immunity cycle scores than low-MPPS group. Seven MPPS-related genes were identified, of which C1QTNF6 was mainly expressed in fibroblasts. High C1QTNF6 expression in fibroblasts was associated with more infiltration of M2 macrophage, Treg cells and less infiltration of NK cells, memory CD8+ T cells. In vitro experiments validated silencing C1QTNF6 in fibroblasts could inhibit M2 macrophage polarization and migration. The study depicted the metabolic landscape of LUAD and constructed a MPPS model to accurately predict prognosis and immunotherapy efficacy. C1QTNF6 was a promising target to regulate M2 macrophage polarization and migration.
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Affiliation(s)
- Yong Liu
- Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong, China
| | - Xiangwei Zhang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Zhaofei Pang
- Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Yadong Wang
- Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong, China
| | - Haotian Zheng
- Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong, China
| | - Guanghui Wang
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
- Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Kai Wang
- Institute of Oncology, Shandong Provincial Hospital, Shandong University, Jinan 250021, Shandong, China
| | - Jiajun Du
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
- Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
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Kuznetsova AB, Kolesova EP, Parodi A, Zamyatnin AA, Egorova VS. Reprogramming Tumor-Associated Macrophage Using Nanocarriers: New Perspectives to Halt Cancer Progression. Pharmaceutics 2024; 16:636. [PMID: 38794298 PMCID: PMC11124960 DOI: 10.3390/pharmaceutics16050636] [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: 04/08/2024] [Revised: 05/03/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Cancer remains a significant challenge for public healthcare systems worldwide. Within the realm of cancer treatment, considerable attention is focused on understanding the tumor microenvironment (TME)-the complex network of non-cancerous elements surrounding the tumor. Among the cells in TME, tumor-associated macrophages (TAMs) play a central role, traditionally categorized as pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. Within the TME, M2-like TAMs can create a protective environment conducive to tumor growth and progression. These TAMs secrete a range of factors and molecules that facilitate tumor angiogenesis, increased vascular permeability, chemoresistance, and metastasis. In response to this challenge, efforts are underway to develop adjuvant therapy options aimed at reprogramming TAMs from the M2 to the anti-tumor M1 phenotype. Such reprogramming holds promise for suppressing tumor growth, alleviating chemoresistance, and impeding metastasis. Nanotechnology has enabled the development of nanoformulations that may soon offer healthcare providers the tools to achieve targeted drug delivery, controlled drug release within the TME for TAM reprogramming and reduce drug-related adverse events. In this review, we have synthesized the latest data on TAM polarization in response to TME factors, highlighted the pathological effects of TAMs, and provided insights into existing nanotechnologies aimed at TAM reprogramming and depletion.
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Affiliation(s)
- Alyona B. Kuznetsova
- Scientific Center for Translation Medicine, Sirius University of Science and Technology, 354340 Sochi, Russia; (A.B.K.); (E.P.K.); (A.P.)
| | - Ekaterina P. Kolesova
- Scientific Center for Translation Medicine, Sirius University of Science and Technology, 354340 Sochi, Russia; (A.B.K.); (E.P.K.); (A.P.)
| | - Alessandro Parodi
- Scientific Center for Translation Medicine, Sirius University of Science and Technology, 354340 Sochi, Russia; (A.B.K.); (E.P.K.); (A.P.)
| | - Andrey A. Zamyatnin
- Scientific Center for Translation Medicine, Sirius University of Science and Technology, 354340 Sochi, Russia; (A.B.K.); (E.P.K.); (A.P.)
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- Department of Biological Chemistry, Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Vera S. Egorova
- Scientific Center for Translation Medicine, Sirius University of Science and Technology, 354340 Sochi, Russia; (A.B.K.); (E.P.K.); (A.P.)
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Li Y, Ren X, Gao W, Cai R, Wu J, Liu T, Chen X, Jiang D, Chen C, Cheng Q, Wu A, Cheng W. The biological behavior and clinical outcome of pituitary adenoma are affected by the microenvironment. CNS Neurosci Ther 2024; 30:e14729. [PMID: 38738958 PMCID: PMC11090080 DOI: 10.1111/cns.14729] [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: 07/22/2023] [Revised: 02/25/2024] [Accepted: 03/31/2024] [Indexed: 05/14/2024] Open
Abstract
BACKGROUND Pituitary adenoma is one of the most common brain tumors. Most pituitary adenomas are benign and can be cured by surgery and/or medication. However, some pituitary adenomas show aggressive growth with a fast growth rate and are resistant to conventional treatments such as surgery, drug therapy, and radiation therapy. These tumors, referred to as refractory pituitary adenomas, often relapse or regrow in the early postoperative period. The tumor microenvironment (TME) has recently been identified as an important factor affecting the biological manifestations of tumors and acts as the main battlefield between the tumor and the host immune system. MAIN BODY In this review, we focus on describing TME in pituitary adenomas and refractory pituitary adenomas. Research on the immune microenvironment of pituitary adenomas is currently focused on immune cells such as macrophages and lymphocytes, and extensive research and experimental verifications are still required regarding other components of the TME. In particular, studies are needed to determine the role of the TME in the specific biological behaviors of refractory pituitary adenomas, such as high invasion, fast recurrence rate, and high tolerance to traditional treatments and to identify the mechanisms involved. CONCLUSION Overall, we summarize the similarities and differences between the TME of pituitary adenomas and refractory pituitary adenomas as well as the changes in the biological behavior of pituitary adenomas that may be caused by the microenvironment. These changes greatly affect the outcome of patients.
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Affiliation(s)
- Yuhe Li
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Xiufang Ren
- Department of PathologyShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Wei Gao
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Ruikai Cai
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Jianqi Wu
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Tianqi Liu
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Xin Chen
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Daoming Jiang
- Shenyang ShenDa Endoscopy Co., Ltd.ShenyangLiaoningChina
| | - Chong Chen
- Shenyang ShenDa Endoscopy Co., Ltd.ShenyangLiaoningChina
| | - Quan Cheng
- Department of Neurosurgery, Xiangya HospitalCentral South UniversityChangshaHunanChina
- National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Anhua Wu
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Wen Cheng
- Department of NeurosurgeryShengjing Hospital of China Medical UniversityShenyangLiaoningChina
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Chen Y, Cai S, Li X, Zhang J, Wei L, Wang S. MRI 3D SPACE T2WI for Pituitary Adenoma Cavernous Sinus Invasion Diagnosis. World Neurosurg 2024; 185:e1257-e1267. [PMID: 38514027 DOI: 10.1016/j.wneu.2024.03.066] [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: 02/27/2024] [Accepted: 03/14/2024] [Indexed: 03/23/2024]
Abstract
OBJECTIVE This study aims to assess the utility of magnetic resonance imaging (MRI) 3D SPACE T2-weighted imaging (T2WI) sequences in evaluating cavernous sinus invasion by pituitary adenomas. METHODS Data were collected from patients who underwent continuous pituitary MRIexaminations at the Medical Imaging Center of our hospital from October 2019 to February 2021. Eligible cases were evaluated for sagittal and axial T1WI sequences, coronal 3D SPACE T2WI sequences, and sagittal and coronal enhanced T1-weighted imaging (T1WI) sequences using the INFINITT PACS workstation. The Wilcoxon signed-rank test for paired samples and the Mann-Whitney U test for 2 independent samples were used to statistically analyze differences in image quality scores among various groups. In addition, the sensitivity, specificity, positive predictive value, and negative predictive value of each observation index were compared with intraoperative results. RESULTS 3D SPACE T2WI showed superior cavernous sinus imaging quality compared with contrast enhanced T1WI and T2WI plain scans (P < 0.05). The sensitivity, specificity, positive predictive value, and negative predictive value were 100%, 90.0%, 55.60%, and 100.0%, respectively. The accuracy for pituitary adenoma invasiveness diagnosis based on cavernous sinus medial wall integrity was 94.40%. CONCLUSIONS The imaging quality of the medial wall of the cavernous sinus on the 3D SPACE T2WI plain scan sequence surpassed that of contrast enhanced T1WI TSE-enhanced scans and T2WI TSE plain scans. The continuous observation of the medial wall of the cavernous sinus using this sequence holds great diagnostic value for assessing cavernous sinus invasion by pituitary adenomas. This strategy is more reliable than traditional MRI observation indicators.
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Affiliation(s)
- Yuyang Chen
- Neurosurgery, Fujian Medical University Fuzhou Clinical Medical College (900th Hospital), Fuzhou, China
| | - Shengyu Cai
- Neurosurgery, Fujian Medical University Fuzhou Clinical Medical College (900th Hospital), Fuzhou, China; Neurosurgery, Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Xiu Li
- Neurosurgery, Fujian Medical University Fuzhou Clinical Medical College (900th Hospital), Fuzhou, China
| | - Jianhe Zhang
- Neurosurgery, Fujian Medical University Fuzhou Clinical Medical College (900th Hospital), Fuzhou, China
| | - Liangfeng Wei
- Neurosurgery, Fujian Medical University Fuzhou Clinical Medical College (900th Hospital), Fuzhou, China
| | - Shousen Wang
- Neurosurgery, Fujian Medical University Fuzhou Clinical Medical College (900th Hospital), Fuzhou, China.
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Vela-Patiño S, Salazar MI, Taniguchi-Ponciano K, Vadillo E, Gomez-Apo E, Escobar-España A, Perez-Koldenkova V, Bonifaz L, Aguilar-Flores C, Marrero-Rodríguez D, Mercado M. The Immune Microenvironment Landscape of Pituitary NeuroEndocrine Tumors, a Transcriptomic Approach. Genes (Basel) 2024; 15:531. [PMID: 38790160 PMCID: PMC11120841 DOI: 10.3390/genes15050531] [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: 03/25/2024] [Revised: 04/08/2024] [Accepted: 04/22/2024] [Indexed: 05/26/2024] Open
Abstract
Pituitary neuroendocrine tumors (PitNET) are known to be variably infiltrated by different immune cells. Nonetheless, their role in pituitary oncogenesis has only begun to be unveiled. The immune microenvironment could determine the biological and clinical behavior of a neoplasm and may have prognostic implications. To evaluate the expression of immune-related genes and to correlate such expression with the presence of infiltrating immune cells in forty-two PitNETs of different lineages, we performed whole transcriptome analysis and RT-qPCR. Deconvolution analysis was carried out to infer the immune cell types present in each tumor and the presence of immune cells was confirmed by immunofluorescence. We found characteristic expression profiles of immune-related genes including those encoding interleukins and chemokines for each tumor lineage. Genes such as IL4-I1, IL-36A, TIRAP, IL-17REL, and CCL5 were upregulated in all PitNETS, whereas IL34, IL20RA, and IL-2RB characterize the NR5A1-, TBX19-, and POU1F1-derived tumors, respectively. Transcriptome deconvolution analysis showed that M2 macrophages, CD4+ T cells, CD8+ T cells, NK cells, and neutrophils can potentially infiltrate PitNET. Furthermore, CD4+ and CD8+ T cells and NK cells infiltration was validated by immunofluorescence. Expression of CCL18, IL-5RA, and HLA-B as well as macrophage tumor infiltration could identify patients who can potentially benefit from treatment with immune checkpoint inhibitors.
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Affiliation(s)
- Sandra Vela-Patiño
- Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, Ciudad de México 06720, Mexico (K.T.-P.)
- Laboratorio Nacional de Vacunología y Virus Tropicales, Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México 11350, Mexico
| | - Ma. Isabel Salazar
- Laboratorio Nacional de Vacunología y Virus Tropicales, Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México 11350, Mexico
| | - Keiko Taniguchi-Ponciano
- Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, Ciudad de México 06720, Mexico (K.T.-P.)
| | - Eduardo Vadillo
- Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, Ciudad de México 06720, Mexico
| | - Erick Gomez-Apo
- Área de Neuropatología, Servicio de Anatomía Patológica, Hospital General de México “Dr. Eduardo Liceaga”, Ciudad de México 06720, Mexico; (E.G.-A.)
| | - Aurea Escobar-España
- Área de Neuropatología, Servicio de Anatomía Patológica, Hospital General de México “Dr. Eduardo Liceaga”, Ciudad de México 06720, Mexico; (E.G.-A.)
| | - Vadim Perez-Koldenkova
- Laboratorio Nacional de Microscopia Avanzada, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, Ciudad de México 06720, Mexico
| | - Laura Bonifaz
- Unidad de Investigación Médica en Inmunoquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, Ciudad de México 06720, Mexico
- Coordinación de Investigación en Salud, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, Ciudad de México 06720, Mexico
| | - Cristina Aguilar-Flores
- Unidad de Investigación Médica en Inmunología, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, Ciudad de México 06720, Mexico
| | - Daniel Marrero-Rodríguez
- Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, Ciudad de México 06720, Mexico (K.T.-P.)
| | - Moises Mercado
- Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, Ciudad de México 06720, Mexico (K.T.-P.)
- Centro de Cancer, Hospital American British Cowdray, Sur 136 116, Las Américas, Álvaro Obregón, Ciudad de México 01120, Mexico
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Lin S, Dai Y, Han C, Han T, Zhao L, Wu R, Liu J, Zhang B, Huang N, Liu Y, Lai S, Shi J, Wang Y, Lou M, Xie J, Cheng Y, Tang H, Yao H, Fang H, Zhang Y, Wu X, Shen L, Ye Y, Xue L, Wu ZB. Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage-tumor interaction axes among different lineages of pituitary neuroendocrine tumors. Genome Med 2024; 16:60. [PMID: 38658971 PMCID: PMC11040908 DOI: 10.1186/s13073-024-01325-4] [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: 10/14/2023] [Accepted: 03/26/2024] [Indexed: 04/26/2024] Open
Abstract
BACKGROUND Pituitary neuroendocrine tumors (PitNETs) are common gland neoplasms demonstrating distinctive transcription factors. Although the role of immune cells in PitNETs has been widely recognized, the precise immunological environment and its control over tumor cells are poorly understood. METHODS The heterogeneity, spatial distribution, and clinical significance of macrophages in PitNETs were analyzed using single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, spatial transcriptomics, immunohistochemistry, and multiplexed quantitative immunofluorescence (QIF). Cell viability, cell apoptosis assays, and in vivo subcutaneous xenograft experiments have confirmed that INHBA-ACVR1B influences the process of tumor cell apoptosis. RESULTS The present study evaluated scRNA-seq data from 23 PitNET samples categorized into 3 primary lineages. The objective was to explore the diversity of tumors and the composition of immune cells across these lineages. Analyzed data from scRNA-seq and 365 bulk RNA sequencing samples conducted in-house revealed the presence of three unique subtypes of tumor immune microenvironment (TIME) in PitNETs. These subtypes were characterized by varying levels of immune infiltration, ranging from low to intermediate to high. In addition, the NR5A1 lineage is primarily associated with the subtype characterized by limited infiltration of immune cells. Tumor-associated macrophages (TAMs) expressing CX3CR1+, C1Q+, and GPNMB+ showed enhanced contact with tumor cells expressing NR5A1 + , TBX19+, and POU1F1+, respectively. This emphasizes the distinct interaction axes between TAMs and tumor cells based on their lineage. Moreover, the connection between CX3CR1+ macrophages and tumor cells via INHBA-ACVR1B regulates tumor cell apoptosis. CONCLUSIONS In summary, the different subtypes of TIME and the interaction between TAM and tumor cells offer valuable insights into the control of TIME that affects the development of PitNET. These findings can be utilized as prospective targets for therapeutic interventions.
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Affiliation(s)
- Shaojian Lin
- Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Neurosurgery, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yuting Dai
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Rujin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Changxi Han
- Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tianyi Han
- Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Linfeng Zhao
- Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Renyan Wu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianyue Liu
- Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bo Zhang
- Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ning Huang
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yanting Liu
- Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shujing Lai
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jintong Shi
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Wang
- Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meiqing Lou
- Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Xie
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yijun Cheng
- Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Tang
- Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong Yao
- Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hai Fang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Rujin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Zhang
- Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xuefeng Wu
- Department of Neurosurgery, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Immunology, Department of Immunology and Microbiology and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Shen
- Department of Neurosurgery, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Youqiong Ye
- Department of Neurosurgery, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Li Xue
- Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Department of Neurosurgery, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Shanghai Center for Brain Science and Brain-Inspired Technology, Shanghai, China.
| | - Zhe Bao Wu
- Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Department of Neurosurgery, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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Xiong H, Zhai Y, Meng Y, Wu Z, Qiu A, Cai Y, Wang G, Yang L. Acidosis activates breast cancer ferroptosis through ZFAND5/SLC3A2 signaling axis and elicits M1 macrophage polarization. Cancer Lett 2024; 587:216732. [PMID: 38360142 DOI: 10.1016/j.canlet.2024.216732] [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: 09/12/2023] [Revised: 02/08/2024] [Accepted: 02/09/2024] [Indexed: 02/17/2024]
Abstract
Acidosis is involved in multiple pathways in tumor cells and immune cells among the tumor microenvironment (TME). Ferroptosis is a nonapoptotic and iron-dependent form of cell death characterized by accumulation of lipid peroxidation involved in various cancers. The role of ferroptosis in the breast cancer (BC) acidic microenvironment remains unrevealed. Here, we reported that short-term acidosis induced ferroptosis of BC cells in the zinc finger AN1-type domain 5 (ZFAND5)/solute carrier family 3 member 2 (SLC3A2) dependent manner to suppress tumor growth using in silico and multiple biological methods. Mechanistically, we demonstrated that short-term acidosis increased total/lipid reactive oxygen species (ROS) level, decreased glutathione (GSH) level and induced the morphological changes of mitochondria. Specifically, acidosis restrained the protein stability of SLC3A2 by promoting its ubiquitination process. The prognostic analysis showed that higher expression of ZFAND5 and lower expression of SLC3A2 were correlated with longer overall survival of BC patients, respectively. Furthermore, in combination with ferroptosis agonist metformin, short-term acidosis could synergistically inhibit viability and enhance the ferroptosis of BC cells. Meanwhile, by the exploration of immune cells, short-term acidosis also induced M1 macrophage polarization, triggering processes of phagocytosis and ferroptosis in BC cells. This study demonstrated that short-term acidosis induced BC cell ferroptosis through ZFAND5/SLC3A2 signaling axis and promoted phagocytosis and ferroptosis of BC cells with M1 macrophage polarization, which might be a new mechanism for BC therapy.
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Affiliation(s)
- Hanchu Xiong
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yanan Zhai
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yimei Meng
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Zhuazhua Wu
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Anchen Qiu
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yu Cai
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Geyi Wang
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Liu Yang
- Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
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Yan C, Yang Z, Chen P, Yeh Y, Sun C, Xie T, Huang W, Zhang X. GPR65 sensing tumor-derived lactate induces HMGB1 release from TAM via the cAMP/PKA/CREB pathway to promote glioma progression. J Exp Clin Cancer Res 2024; 43:105. [PMID: 38576043 PMCID: PMC10993467 DOI: 10.1186/s13046-024-03025-8] [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: 11/08/2023] [Accepted: 03/23/2024] [Indexed: 04/06/2024] Open
Abstract
BACKGROUND Lactate has emerged as a critical regulator within the tumor microenvironment, including glioma. However, the precise mechanisms underlying how lactate influences the communication between tumor cells and tumor-associated macrophages (TAMs), the most abundant immune cells in glioma, remain poorly understood. This study aims to elucidate the impact of tumor-derived lactate on TAMs and investigate the regulatory pathways governing TAM-mediated tumor-promotion in glioma. METHODS Bioinformatic analysis was conducted using datasets from TCGA and CGGA. Single-cell RNA-seq datasets were analyzed by using UCSC Cell Browser and Single Cell Portal. Cell proliferation and mobility were evaluated through CCK8, colony formation, wound healing, and transwell assays. Western blot and immunofluorescence staining were applied to assess protein expression and cell distribution. RT-PCR and ELISA were employed to identify the potential secretory factors. Mechanistic pathways were explored by western blotting, ELISA, shRNA knockdown, and specific inhibitors and activators. The effects of pathway blockades were further assessed using subcutaneous and intracranial xenograft tumor models in vivo. RESULTS Elevated expressions of LDHA and MCT1 were observed in glioma and exhibited a positive correlation with M2-type TAM infiltration. Lactate derived from glioma cells induced TAMs towards M2-subtype polarization, subsequently promoting glioma cells proliferation, migration, invasion, and mesenchymal transition. GPR65, highly expressed on TAMs, sensed lactate-stimulation in the TME, fueling glioma cells malignant progression through the secretion of HMGB1. GPR65 on TAMs triggered HMGB1 release in response to lactate stimulation via the cAMP/PKA/CREB signaling pathway. Disrupting this feedback loop by GPR65-knockdown or HMGB1 inhibition mitigated glioma progression in vivo. CONCLUSION These findings unveil the intricate interplay between TAMs and tumor cells mediated by lactate and HMGB1, driving tumor progression in glioma. GPR65, selectively highly expressed on TAMs in glioma, sensed lactate stimulation and fostered HMGB1 secretion via the cAMP/PKA/CREB signaling pathway. Blocking this feedback loop presents a promising therapeutic strategy for GBM.
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Affiliation(s)
- Chaolong Yan
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zijiang Yang
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Pin Chen
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuyang Yeh
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chongjing Sun
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tao Xie
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Wei Huang
- State Key Laboratory of Neuroscience, Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
| | - Xiaobiao Zhang
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, China.
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47
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Yang S, Hu C, Chen X, Tang Y, Li J, Yang H, Yang Y, Ying B, Xiao X, Li SZ, Gu L, Zhu Y. Crosstalk between metabolism and cell death in tumorigenesis. Mol Cancer 2024; 23:71. [PMID: 38575922 PMCID: PMC10993426 DOI: 10.1186/s12943-024-01977-1] [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: 06/17/2023] [Accepted: 03/02/2024] [Indexed: 04/06/2024] Open
Abstract
It is generally recognized that tumor cells proliferate more rapidly than normal cells. Due to such an abnormally rapid proliferation rate, cancer cells constantly encounter the limits of insufficient oxygen and nutrient supplies. To satisfy their growth needs and resist adverse environmental events, tumor cells modify the metabolic pathways to produce both extra energies and substances required for rapid growth. Realizing the metabolic characters special for tumor cells will be helpful for eliminating them during therapy. Cell death is a hot topic of long-term study and targeting cell death is one of the most effective ways to repress tumor growth. Many studies have successfully demonstrated that metabolism is inextricably linked to cell death of cancer cells. Here we summarize the recently identified metabolic characters that specifically impact on different types of cell deaths and discuss their roles in tumorigenesis.
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Affiliation(s)
- Shichao Yang
- School of Medicine, Chongqing University, Chongqing, 400030, P. R. China
| | - Caden Hu
- School of Medicine, Chongqing University, Chongqing, 400030, P. R. China
| | - Xiaomei Chen
- School of Medicine, Chongqing University, Chongqing, 400030, P. R. China
| | - Yi Tang
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, P. R. China
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, P. R. China
| | - Juanjuan Li
- Department of breast and thyroid surgery, Renmin hospital of Wuhan University, Wuhan, 430060, P. R. China
| | - Hanqing Yang
- School of Medicine, Chongqing University, Chongqing, 400030, P. R. China
| | - Yi Yang
- Institute of Pathology and Southwest Cancer Center, The First Affiliated Hospital, Key Laboratory of Tumor Immunopathology, Third Military Medical University (Army Medical University, Ministry of Education of China, Chongqing, 400038, P. R. China
| | - Binwu Ying
- Department of Laboratory Medicine/Clinical Laboratory Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, P. R. China.
| | - Xue Xiao
- Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, P. R. China.
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, P. R. China.
| | - Shang-Ze Li
- School of Medicine, Chongqing University, Chongqing, 400030, P. R. China.
| | - Li Gu
- Department of Laboratory Medicine/Clinical Laboratory Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, P. R. China.
| | - Yahui Zhu
- School of Medicine, Chongqing University, Chongqing, 400030, P. R. China.
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Zhang Y, Nie Y, Liu X, Wan X, Shi Y, Zhang K, Wu P, He J. Tumor metabolic crosstalk and immunotherapy. Clin Transl Oncol 2024; 26:797-807. [PMID: 37740892 DOI: 10.1007/s12094-023-03304-4] [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: 04/13/2023] [Accepted: 08/08/2023] [Indexed: 09/25/2023]
Abstract
Tumor cells must resist the host's immune system while maintaining growth under harsh conditions of acidity and hypoxia, which indicates that tumors are more robust than normal tissue. Immunotherapeutic agents have little effect on solid tumors, mostly because of the tumor density and the difficulty of penetrating deeply into the tissue to achieve the theoretical therapeutic effect. Various therapeutic strategies targeting the tumor microenvironment (TME) have been developed. Immunometabolic disorders play a dominant role in treatment resistance at both the TME and host levels. Understanding immunometabolic factors and their treatment potential may be a way forward for tumor immunotherapy. Here, we summarize the metabolism of substances that affect tumor progression, the crosstalk between the TME and immunosuppression, and some potential tumor-site targets. We also summarize the progress and challenges of tumor immunotherapy.
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Affiliation(s)
- Yiwen Zhang
- State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Yueli Nie
- State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Xiyu Liu
- State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- School of Pharmacy, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Xitian Wan
- State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Yuanyuan Shi
- State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Keyong Zhang
- State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Pan Wu
- State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China
- School of Pharmacy, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Jian He
- State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, 530021, Guangxi, China.
- School of Pharmacy, Guangxi Medical University, Nanning, 530021, Guangxi, China.
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49
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Ajam-Hosseini M, Heydari R, Rasouli M, Akhoondi F, Asadi Hanjani N, Bekeschus S, Doroudian M. Lactic acid in macrophage polarization: A factor in carcinogenesis and a promising target for cancer therapy. Biochem Pharmacol 2024; 222:116098. [PMID: 38431231 DOI: 10.1016/j.bcp.2024.116098] [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: 11/24/2023] [Revised: 02/19/2024] [Accepted: 02/26/2024] [Indexed: 03/05/2024]
Abstract
Cancer remains a formidable challenge, continually revealing its intricate nature and demanding novel treatment approaches. Within this intricate landscape, the tumor microenvironment and its dynamic components have gained prominence, particularly macrophages that can adopt diverse polarization states, exerting a profound influence on cancer progression. Recent revelations have spotlighted lactic acid as a pivotal player in this complex interplay. This review systematically explores lactic acid's multifaceted role in macrophage polarization, focusing on its implications in carcinogenesis. We commence by cultivating a comprehensive understanding of the tumor microenvironment and the pivotal roles played by macrophages. The dynamic landscape of macrophage polarization, typified by M1 and M2 phenotypes, is dissected to reveal its substantial impact on tumor progression. Lactic acid, a metabolic byproduct, emerges as a key protagonist, and we meticulously unravel the mechanisms underpinning its generation within cancer cells, shedding light on its intimate association with glycolysis and its transformative effects on the tumor microenvironment. Furthermore, we decipher the intricate molecular framework that underlies lactic acid's pivotal role in facilitating macrophage polarization. Our review underscores lactic acid's dual role in carcinogenesis, orchestrating tumor growth and immune modulation within the tumor microenvironment, thereby profoundly influencing the balance between pro-tumor and anti-tumor immune responses. This duality highlights the therapeutic potential of selectively manipulating lactic acid metabolism for cancer treatment. Exploring strategies to inhibit lactic acid production by tumor cells, novel approaches to impede lactic acid transport in the tumor microenvironment, and the burgeoning field of immunotherapeutic cancer therapies utilizing lactic acid-induced macrophage polarization form the core of our investigation.
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Affiliation(s)
- Mobarakeh Ajam-Hosseini
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Romina Heydari
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Milad Rasouli
- Department of Physics, Kharazmi University, Tehran, Iran; Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Fatemeh Akhoondi
- Department of Molecular Biology of the Cell, Faculty of Bioscience, University of Milan, Milan, Italy
| | - Niloofar Asadi Hanjani
- Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran; Student Research Committee, Pasteur Institute of Iran, Tehran, Iran
| | - Sander Bekeschus
- ZIK plasmatis, Leibniz Institute for Plasma Science and Technology (INP), Felix-Hausdorff-Str 2, 17489 Greifswald, Germany; Clinic and Policlinic for Dermatology and Venerology, Rostock University Medical Center, Strempelstr. 13, 18057 Rostock, Germany
| | - Mohammad Doroudian
- Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.
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Gao F, Xue C, Dong J, Lu X, Yang N, Ou C, Mou X, Zhang YZ, Dong X. Tumor Microenvironment-Induced Drug Depository for Persistent Antitumor Chemotherapy and Immune Activation. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2307736. [PMID: 38009506 DOI: 10.1002/smll.202307736] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/16/2023] [Indexed: 11/29/2023]
Abstract
Herein, a drug-loading nanosystem that can in situ form drug depository for persistent antitumor chemotherapy and immune regulation is designed and built. The system (DOX@MIL-LOX@AL) is fabricated by packaging alginate on the surface of Doxorubicin (DOX) and lactate oxidase (LOX) loaded MIL-101(Fe)-NH2 nanoparticle, which can easily aggregate in the tumor microenvironment through the cross-linking with intratumoral Ca2+. Benefiting from the tumor retention ability, the fast-formed drug depository will continuously release DOX and Fe ions through the ATP-triggered slow degradation, thus realizing persistent antitumor chemotherapy and immune regulation. Meanwhile, LOX in the non-aggregated nanoparticles is able to convert the lactic acid to H2O2, which will be subsequently decomposed into ·OH by Fe ions to further enhance the DOX-induced immunogenic death effect of tumor cells. Together, with the effective consumption of immunosuppressive lactic acid, long-term chemotherapy, and oxidation therapy, DOX@MIL-LOX@AL can execute high-performance antitumor chemotherapy and immune activation with only one subcutaneous administration.
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Affiliation(s)
- Fan Gao
- Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, School of Environmental Science and Engineering, Nanjing University of Information Science & Technology, Nanjing, 210044, China
- Institute of Advanced Materials and Flexible Electronics (IAMFE), School of Chemistry and Materials Science, Nanjing University of Information Science & Technology, Nanjing, 210044, China
| | - Chun Xue
- Institute of Advanced Materials and Flexible Electronics (IAMFE), School of Chemistry and Materials Science, Nanjing University of Information Science & Technology, Nanjing, 210044, China
| | - Jianhui Dong
- Institute of Advanced Materials and Flexible Electronics (IAMFE), School of Chemistry and Materials Science, Nanjing University of Information Science & Technology, Nanjing, 210044, China
| | - Xinxin Lu
- Institute of Advanced Materials and Flexible Electronics (IAMFE), School of Chemistry and Materials Science, Nanjing University of Information Science & Technology, Nanjing, 210044, China
| | - Nan Yang
- Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Changjin Ou
- Institute of Advanced Materials and Flexible Electronics (IAMFE), School of Chemistry and Materials Science, Nanjing University of Information Science & Technology, Nanjing, 210044, China
| | - Xiaozhou Mou
- Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Cancer Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Yi-Zhou Zhang
- Institute of Advanced Materials and Flexible Electronics (IAMFE), School of Chemistry and Materials Science, Nanjing University of Information Science & Technology, Nanjing, 210044, China
| | - Xiaochen Dong
- Key Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials (IAM), Nanjing Tech University (NanjingTech), Nanjing, 211816, China
- School of Chemistry & Materials Science, Jiangsu Normal University, Xuzhou, 221116, China
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