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Neamah AS, Wadan AHS, Lafta FM, Elakwa DES. The potential role of targeting the leptin receptor as a treatment for breast cancer in the context of hyperleptinemia: a literature review. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:3451-3466. [PMID: 39565396 DOI: 10.1007/s00210-024-03592-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 10/31/2024] [Indexed: 11/21/2024]
Abstract
Since cancer is becoming a leading cause of death worldwide, efforts should be concentrated on understanding its underlying biological alterations that would be utilized in disease management, especially prevention strategies. Within this context, multiple bodies of evidence have highlighted leptin's practical and promising role, a peptide hormone extracted from adipose and fatty tissues with other adipokines, in promoting the proliferation, migration, and metastatic invasion of breast carcinoma cells. Excessive blood leptin levels and hyperleptinemia increase body fat content and stimulate appetite. Also, high leptin level is believed to be associated with several conditions, including overeating, emotional stress, inflammation, obesity, and gestational diabetes. It has been noted that when leptin has impaired signaling in CNS, causing the lack of its normal function in energy balance, it results in leptin resistance, leading to a rise in its concentration in peripheral tissues. Our research paper will shed highlighting on potentially targeting the leptin receptor and its cellular signaling in suppressing breast cancer progression.
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Affiliation(s)
- Abbas S Neamah
- Department of Biology, College of Sciences, University of Baghdad, Baghdad, Iraq.
| | - Al-Hassan Soliman Wadan
- Oral Biology Department, Faculty of Dentistry, Galala University, Galala Plateau, Attaka, Suez Governorate, 15888, Egypt
| | - Fadhel M Lafta
- Department of Biology, College of Sciences, University of Baghdad, Baghdad, Iraq
| | - Doha El-Sayed Elakwa
- Department of Biochemistry & Molecular Biology, Faculty of Pharmacy for Girls, Al-Azhar University, Cairo, Egypt
- Department of Biochemistry, Faculty of Pharmacy, Sinai University, Kantra Branch, Ismailia, Egypt
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2
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Liu Q, Jia W, Zhang Y, Lu J, Luo Q, Yang L, Wan D. Causal effects of blood cells on breast cancer: Evidence from bidirectional Mendelian randomization combined with meta-analysis. Medicine (Baltimore) 2025; 104:e41545. [PMID: 39960903 PMCID: PMC11835135 DOI: 10.1097/md.0000000000041545] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 01/28/2025] [Indexed: 02/20/2025] Open
Abstract
Recent studies suggest blood cells influence breast cancer, but no Mendelian randomization (MR) studies have confirmed a causal relationship between specific blood cell phenotypes and breast cancer. MR analysis of blood cell phenotypes used breast cancer data from Finngen R11, UKB, and open genome-wide association study databases. Meta-analyzed inverse variance weighted results were adjusted for multiple comparisons. The reverse relationship was also explored. MR and meta-analysis identified significant associations between specific blood cell phenotypes and breast cancer: neutrophil perturbation response (side fluorescence standard deviation of neutrophil 4 in response to alhydrogel perturbation): odds ratio (OR) = 0.967, P = .0009; neutrophil perturbation response (forward scatter median of neutrophil 4 in response to Pam3CSK4 perturbation): OR = 0.972, P = .031; white blood cell perturbation response (side scatter coefficient of variation of WBC 2 in response to nigericin perturbation): OR = 0.972, P = .031; white blood cell perturbation response (forward scatter coefficient of variation of WBC in response to Pam3CSK4 perturbation): OR = 1.042, P = 8.15 × 10-5. And there was no reverse result. Neutrophil perturbation response (side fluorescence standard deviation of neutrophil 4 in response to alhydrogel perturbation) and white blood cell perturbation response (side scatter coefficient of variation of WBC 2 in response to nigericin perturbation) are protective factors for breast cancer. Conversely, neutrophil perturbation response (forward scatter median of neutrophil 4 in response to Pam3CSK4 perturbation) and white blood cell perturbation response (forward scatter coefficient of variation of WBC in response to Pam3CSK4 perturbation) are risk factors for breast cancer.
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Affiliation(s)
- Qi Liu
- Department of Oncology, Anhui Zhongke Gengjiu Hospital, Hefei, Anhui Province, China
| | - Wei Jia
- Department of Medical Oncology, The First Affiliated Hospital of USTC, Hefei, Anhui Province, China
| | - Yi Zhang
- Department of Oncology, Anhui Zhongke Gengjiu Hospital, Hefei, Anhui Province, China
| | - Jun Lu
- Department of Oncology, Anhui Zhongke Gengjiu Hospital, Hefei, Anhui Province, China
| | - Qingbin Luo
- Department of Oncology, Anhui Zhongke Gengjiu Hospital, Hefei, Anhui Province, China
| | - Lin Yang
- Department of Oncology, Anhui Zhongke Gengjiu Hospital, Hefei, Anhui Province, China
| | - Dongdong Wan
- Department of Medical Oncology, Nantong Haimen District People’s Hospital, Nantong, Jiangsu Province, China
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3
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Cesana B, Cochet C, Filhol O. New players in the landscape of renal cell carcinoma bone metastasis and therapeutic opportunities. Int J Cancer 2025; 156:475-487. [PMID: 39306698 PMCID: PMC11622000 DOI: 10.1002/ijc.35181] [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: 05/02/2024] [Revised: 08/09/2024] [Accepted: 08/20/2024] [Indexed: 12/07/2024]
Abstract
Approximately one-third of advanced renal cell carcinoma (RCC) patients develop osteolytic bone metastases, leading to skeletal complications. In this review, we first provide a comprehensive perspective of seminal studies on bone metastasis of RCC describing the main molecular modulators and growth factor signaling pathways most important for the RCC-stimulated osteoclast-mediated bone destruction. We next focus on newer developments revealing with in-depth details, the bidirectional interplay between renal cancer cells and the immune and stromal microenvironment that can through epigenetic reprogramming, profoundly affect the behaviors of transformed cells. Understanding their mechanistic interactions is of paramount importance for advancing both fundamental and translational research. These new investigations into the landscape of RCC-bone metastasis offer novel insights and identify potential avenues for future therapeutic interventions.
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Affiliation(s)
- Beatrice Cesana
- University Grenoble Alpes, INSERM, CEA, IRIG‐Biosanté, UMR 1292GrenobleFrance
| | - Claude Cochet
- University Grenoble Alpes, INSERM, CEA, IRIG‐Biosanté, UMR 1292GrenobleFrance
| | - Odile Filhol
- University Grenoble Alpes, INSERM, CEA, IRIG‐Biosanté, UMR 1292GrenobleFrance
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4
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Yasir M, Park J, Han ET, Han JH, Park WS, Hassan M, Kloczkowski A, Chun W. Discovery of novel TACE inhibitors using graph convolutional network, molecular docking, molecular dynamics simulation, and Biological evaluation. PLoS One 2024; 19:e0315245. [PMID: 39729480 DOI: 10.1371/journal.pone.0315245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 11/21/2024] [Indexed: 12/29/2024] Open
Abstract
The increasing utilization of deep learning models in drug repositioning has proven to be highly efficient and effective. In this study, we employed an integrated deep-learning model followed by traditional drug screening approach to screen a library of FDA-approved drugs, aiming to identify novel inhibitors targeting the TNF-α converting enzyme (TACE). TACE, also known as ADAM17, plays a crucial role in the inflammatory response by converting pro-TNF-α to its active soluble form and cleaving other inflammatory mediators, making it a promising target for therapeutic intervention in diseases such as rheumatoid arthritis. Reference datasets containing active and decoy compounds specific to TACE were obtained from the DUD-E database. Using RDKit, a cheminformatics toolkit, we extracted molecular features from these compounds. We applied the GraphConvMol model within the DeepChem framework, which utilizes graph convolutional networks, to build a predictive model based on the DUD-E datasets. Our trained model was subsequently used to predict the TACE inhibitory potential of FDA-approved drugs. From these predictions, Vorinostat was identified as a potential TACE inhibitor. Moreover, molecular docking and molecular dynamics simulation were conducted to validate these findings, using BMS-561392 as a reference TACE inhibitor. Vorinostat, originally an FDA-approved drug for cancer treatment, exhibited strong binding interactions with key TACE residues, suggesting its repurposing potential. Biological evaluation with RAW 264.7 cell confirmed the computational results, demonstrating that Vorinostat exhibited comparable inhibitory activity against TACE. In conclusion, our study highlights the capability of deep learning models to enhance virtual screening efforts in drug discovery, efficiently identifying potential candidates for specific targets such as TACE. Vorinostat, as a newly identified TACE inhibitor, holds promise for further exploration and investigation in the treatment of inflammatory diseases like rheumatoid arthritis.
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Affiliation(s)
- Muhammad Yasir
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
| | - Jinyoung Park
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
| | - Eun-Taek Han
- Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
| | - Jin-Hee Han
- Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
| | - Won Sun Park
- Department of Physiology, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
| | - Mubashir Hassan
- The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, Ohio, United States of America
| | - Andrzej Kloczkowski
- The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children's Hospital, Columbus, Ohio, United States of America
| | - Wanjoo Chun
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon, Republic of Korea
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5
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Jackett KN, Browne AT, Aber ER, Clements M, Kaplan RN. How the bone microenvironment shapes the pre-metastatic niche and metastasis. NATURE CANCER 2024; 5:1800-1814. [PMID: 39672975 DOI: 10.1038/s43018-024-00854-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 10/04/2024] [Indexed: 12/15/2024]
Abstract
The bone is a frequent metastatic site, with changes in the mineralized bone and the bone marrow milieu that can also prime other sites for metastasis by educating progenitor cells to support metastatic spread. Stromal and immune populations cooperatively maintain the organizationally complex bone niches and are dysregulated in the presence of a distant primary tumor and metastatic disease. Interrogating the bone niches that facilitate metastatic spread using innovative technologies holds the potential to aid in preventing metastasis in and mediated by the bone. Here, we review recent advances in bone niche biology and its adaptations in the context of cancer.
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Affiliation(s)
- Kailey N Jackett
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Alice T Browne
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Etan R Aber
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Miranda Clements
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Rosandra N Kaplan
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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6
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Huang C, Luo MY, Wen NQ, Chen YM, Zhang LZ, Cao Y. The prognostic implications and oncogenic role of NSUN5 in clear cell renal cell carcinoma. Clin Exp Med 2024; 25:8. [PMID: 39549185 PMCID: PMC11568983 DOI: 10.1007/s10238-024-01507-9] [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: 07/11/2024] [Accepted: 10/16/2024] [Indexed: 11/18/2024]
Abstract
Clear cell renal cell carcinoma (ccRCC), a predominant form of urinary malignancy, requires the identification of reliable biomarkers to enhance both prognostic outcomes and therapeutic developments specific to ccRCC. NSUN5, a member of the NOL1/NOP2/SUN domain (NSUN) family, plays a critical role in RNA stabilization and exhibits widespread expression across various tumor types. However, the exact function of NSUN5 in ccRCC remains insufficiently understood. Data were collated from cohorts of ccRCC patients who underwent nephrectomy, including those from the Cancer Genome Atlas (TCGA) and the Sun Yat-sen University Cancer Center (SYSUCC), to evaluate the clinical relevance of NSUN5. Integrative models based on NSUN5 expression were subsequently developed to predict the prognosis of ccRCC within the TCGA and SYSUCC cohorts. Furthermore, the impact of NSUN5 on RCC cells and its association with cellular senescence were corroborated through in vitro experimental analyses. NSUN5 exhibited elevated expression in both ccRCC patients and renal cancer cell lines, whose upregulation significantly correlated with age, tumor size, TNM stage, WHO/International Society of Urological Pathology (ISUP) grade, presence of necrosis, and a poor prognosis. An accessible nomogram, incorporating NSUN5 along with various clinicopathological parameters, was adept at predicting outcomes for ccRCC patients. Additionally, in vitro findings indicated that reduced expression of NSUN5 enhanced tumor cell senescence and simultaneously inhibiting cell proliferation and migration. These observations suggest that elevated NSUN5 expression is linked to poorer overall survival (OS) and progression-free survival (PFS), positioning NSUN5 as a viable diagnostic and prognostic biomarker in ccRCC.
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Affiliation(s)
- Chan Huang
- Department of Pathology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Mu-Yang Luo
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China
| | - Neng-Qiao Wen
- Department of Pathology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Yu-Man Chen
- Department of Pathology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, People's Republic of China
| | - Li-Zhen Zhang
- Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510062, People's Republic of China.
| | - Yun Cao
- Department of Pathology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, People's Republic of China.
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7
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Sui L, Wang J, Jiang WG, Song X, Ye L. Molecular mechanism of bone metastasis in breast cancer. Front Oncol 2024; 14:1401113. [PMID: 39605887 PMCID: PMC11599183 DOI: 10.3389/fonc.2024.1401113] [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: 03/14/2024] [Accepted: 10/24/2024] [Indexed: 11/29/2024] Open
Abstract
Bone metastasis is a debilitating complication that frequently occurs in the advanced stages of breast cancer. However, the underlying molecular and cellular mechanisms of the bone metastasis remain unclear. Here, we elucidate how bone metastasis arises from tumor cells that detach from the primary lesions and infiltrate into the surrounding tissue, as well as how these cells disseminate to distant sites. Specifically, we elaborate how tumor cells preferentially grow within the bone micro-environment and interact with bone cells to facilitate bone destruction, characterized as osteoclastic bone metastasis, as well as new bone matrix deposition, characterized as osteoblastic bone metastasis. We also updated the current understanding of the molecular mechanisms underlying bone metastasis and reasons for relapse in breast cancer, and also opportunities of developing novel diagnostic approaches and treatment.
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Affiliation(s)
- Laijian Sui
- Department of Orthopedics, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, China
- Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Jing Wang
- Department of Intensive Care Unit, Yantai Yuhuangding Hospital, Yantai, Shandong, China
| | - Wen G. Jiang
- Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Xicheng Song
- Department of Otorhinolaryngol and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, China
| | - Lin Ye
- Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom
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Guan Y, Zhang W, Mao Y, Li S. Nanoparticles and bone microenvironment: a comprehensive review for malignant bone tumor diagnosis and treatment. Mol Cancer 2024; 23:246. [PMID: 39487487 PMCID: PMC11529338 DOI: 10.1186/s12943-024-02161-1] [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: 09/23/2024] [Accepted: 10/17/2024] [Indexed: 11/04/2024] Open
Abstract
Malignant bone tumors, which are difficult to treat with current clinical strategies, originate from bone tissues and can be classified into primary and secondary types. Due to the specificity of the bone microenvironment, the results of traditional means of treating bone tumors are often unsatisfactory, so there is an urgent need to develop new treatments for malignant bone tumors. Recently, nanoparticle-based approaches have shown great potential in diagnosis and treatment. Nanoparticles (NPs) have gained significant attention due to their versatility, making them highly suitable for applications in bone tissue engineering, advanced imaging techniques, and targeted drug delivery. For diagnosis, NPs enhance imaging contrast and sensitivity by integrating targeting ligands, which significantly improve the specific recognition and localization of tumor cells for early detection. For treatment, NPs enable targeted drug delivery, increasing drug accumulation at tumor sites while reducing systemic toxicity. In conclusion, understanding bone microenvironment and using the unique properties of NPs holds great promise in improving disease management, enhancing treatment outcomes, and ultimately improving the quality of life for patients with malignant bone tumors. Further research and development will undoubtedly contribute to the advancement of personalized medicine in the field of bone oncology.
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Affiliation(s)
- Yujing Guan
- Second Ward of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, 110042, China
- The Liaoning Provincial Key Laboratory of Interdisciplinary Research on Gastrointestinal Tumor Combining Medicine with Engineering, Shenyang, Liaoning, 110042, China
- Institute of Cancer Medicine, Faculty of Medicine, Dalian University of Technology, Dalian, Liaoning, 116024, China
| | - Wei Zhang
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province, 110016, P.R. China
| | - Yuling Mao
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province, 110016, P.R. China.
| | - Shenglong Li
- Second Ward of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, 110042, China.
- The Liaoning Provincial Key Laboratory of Interdisciplinary Research on Gastrointestinal Tumor Combining Medicine with Engineering, Shenyang, Liaoning, 110042, China.
- Institute of Cancer Medicine, Faculty of Medicine, Dalian University of Technology, Dalian, Liaoning, 116024, China.
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Jamal I, Smita S, Raman RB, Choudhary V, Atreya K, Choudhary MK, Ranjan A. Undesirable occupants of bone marrow creating a menace: A 4.5-year audit from a tertiary care centre in Eastern India. Niger Med J 2024; 65:1101-1111. [PMID: 39877504 PMCID: PMC11770638 DOI: 10.60787/nmj.v65i6.574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2025] Open
Abstract
Background Bone marrow (BM) in addition to being the origin of primary hematological malignancies is also commonly involved in metastatic solid tumors. Bone marrow examination includes aspiration and biopsy, and it is a well-known procedure not only to diagnose hematological malignancies but also for staging and prognosis of various solid tumors. The presence of metastasis in the bone marrow is of grave prognostic significance and it is imperative to rule out marrow involvement in any malignancy where curative treatment is considered. The study's objectives were to evaluate the clinical, hematological, and biochemical characteristics of patients with BM metastases of solid tumors diagnosed by bone marrow (BM) aspiration and trephine biopsy and to find out the accuracy rate of diagnosing metastatic infiltration between bone marrow aspiration, trephine imprints, and trephine biopsy procedures. Methodology It was a 4.5-year retrospective hospital-based observational study where relevant clinical, biochemical, and hematological parameters including bone marrow aspirate and biopsy were analyzed and compiled from hospital medical records. Results The total number of BMA and trephine biopsies that came during the duration of 4.5 years were 3850 and 2980 respectively. Out of the 3850-bone marrow aspiration and 2980 trephine biopsies received in the dept of Hematology, 305 cases were referred to look for metastatic bone marrow infiltration. Out of these 305 cases, 69 cases showed the presence of metastatic deposits (12.6%). 45 patients (65.2%) were males, and 24 patients (34.7%) were females with M:F ratio of 1.8:1. Most common age group was 51-60 years (31.8%). The most common complaints were fever, body aches, weight loss, and weakness. Clinical examination revealed pallor in 38 out of 69 cases (55%) and organomegaly in 14 cases (20.2%). Microcytic hypochromic anemia (26%) was the most common finding on peripheral blood smear examination followed by pancytopenia (18.8%). The biochemical findings most commonly observed were raised LDH (60.8%), serum PSA (36.3%), and alkaline phosphatase (21.7%). Conclusion Trephine biopsy is a sensitive method for detecting marrow metastasis and should be done in all cases being investigated for this purpose. BMA alone may miss marrow metastases in almost half of cases. Trephine imprint cytology is more sensitive than BMA and can provide rapid diagnoses while waiting for trephine biopsy results.
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Affiliation(s)
- Iffat Jamal
- Department of Pathology (Hematology section), Indira Gandhi Institute of Medical Sciences, Patna, India
| | - Shuchi Smita
- Department of Pathology (Hematology section), Indira Gandhi Institute of Medical Sciences, Patna, India
| | - Ravi Bhushan Raman
- Department of Pathology (Hematology section), Indira Gandhi Institute of Medical Sciences, Patna, India
| | - Vijayanand Choudhary
- Department of Pathology (Hematology section), Indira Gandhi Institute of Medical Sciences, Patna, India
| | - Kshiti Atreya
- Department of Pathology, Indira Gandhi Institute of Medical Sciences, Patna, India
| | - Manoj Kumar Choudhary
- Department of General Medicine, Indira Gandhi Institute of Medical Sciences, Patna, India
| | - Alok Ranjan
- Department Of Medical Oncology, Indira Gandhi Institute of Medical Sciences, Patna, India
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Ruivo J, Tavares I, Pozza DH. Molecular targets in bone cancer pain: a systematic review of inflammatory cytokines. J Mol Med (Berl) 2024; 102:1063-1088. [PMID: 38940936 PMCID: PMC11358194 DOI: 10.1007/s00109-024-02464-2] [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: 03/14/2024] [Revised: 06/06/2024] [Accepted: 06/20/2024] [Indexed: 06/29/2024]
Abstract
Bone cancer pain (BCP) profoundly impacts patient's quality of life, demanding more effective pain management strategies. The aim of this systematic review was to investigate the role of inflammatory cytokines as potential molecular targets in BCP. A systematic search for animal rodent models of bone cancer pain studies was conducted in PubMed, Scopus, and Web of Science. Methodological quality and risk of bias were assessed using the SYRCLE RoB tool. Twenty-five articles met the inclusion criteria, comprising animal studies investigating molecular targets related to inflammatory cytokines in BCP. A low to moderate risk of bias was reported. Key findings in 23 manuscripts revealed upregulated classic pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17, IL-18, IL-33) and chemokines in the spinal cord, periaqueductal gray, and dorsal root ganglia. Interventions targeting these cytokines consistently mitigated pain behaviors. Additionally, it was demonstrated that glial cells, due to their involvement in the release of inflammatory cytokines, emerged as significant contributors to BCP. This systematic review underscores the significance of inflammatory cytokines as potential molecular targets for alleviating BCP. It emphasizes the promise of targeted interventions and advocates for further research to translate these findings into effective therapeutic strategies. Ultimately, this approach holds the potential to enhance the patient's quality of life.
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Affiliation(s)
- Jacinta Ruivo
- Experimental Biology Unit, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319, Porto, Portugal
| | - Isaura Tavares
- Experimental Biology Unit, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319, Porto, Portugal
- Institute for Research and Innovation in Health and IBMC, University of Porto, 4200-135, Porto, Portugal
| | - Daniel H Pozza
- Experimental Biology Unit, Department of Biomedicine, Faculty of Medicine of Porto, University of Porto, 4200-319, Porto, Portugal.
- Institute for Research and Innovation in Health and IBMC, University of Porto, 4200-135, Porto, Portugal.
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11
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Bennett NE, Parker DV, Mangano RS, Baum JE, Northcutt LA, Miller JS, Beadle EP, Rhoades JA. Pharmacologic Hedgehog inhibition modulates the cytokine profile of osteolytic breast cancer cells. J Bone Oncol 2024; 47:100625. [PMID: 39183755 PMCID: PMC11342115 DOI: 10.1016/j.jbo.2024.100625] [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] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 08/27/2024] Open
Abstract
The establishment and progression of bone metastatic breast cancer is supported by immunosuppressive myeloid populations that enable tumor growth by dampening the innate and adaptive immune response. Much work remains to understand how to target these tumor-myeloid interactions to improve treatment outcomes. Noncanonical Hedgehog signaling is an essential component of bone metastatic tumor progression, and prior literature suggests a potential role for Hedgehog signaling and its downstream effector Gli2 in modulating immune responses. In this work, we sought to identify if inhibition of noncanonical Hedgehog signaling alters the cytokine profile of osteolytic breast cancer cells and the subsequent communication between the tumor cells and myeloid cells. Examination of large patient databases revealed significant relationships between Gli2 expression and expression of markers of myeloid maturation and activation as well as cytokine expression. We found that treatment with HPI-1 reduced tumor cell expression of numerous cytokine genes, including CSF1, CSF2, and CSF3, as well as CCL2 and IL6. Secreted CSF-1 (M-CSF) was also reduced by treatment. Changes in tumor-secreted factors resulted in polarization of THP-1 monocytes toward a proinflammatory phenotype, characterized by increased CD14 and CD40 surface marker expression. We therefore propose M-CSF as a novel target of Hedgehog inhibition with potential future applications in altering the immune microenvironment in addition to its known roles in reducing tumor-induced bone disease.
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Affiliation(s)
- Natalie E. Bennett
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, United States
- Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
- United States Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States
- Medical Scientist Training Program, Vanderbilt University, Nashville, TN, United States
| | - Dominique V. Parker
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, United States
- Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
- United States Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States
| | - Rachel S. Mangano
- Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
- United States Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States
- Interdisciplinary Graduate Program in Biological and Biomedical Sciences, Vanderbilt University, Nashville, TN, United States
| | - Jennifer E. Baum
- Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
- United States Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States
- Master’s Program in Biomedical Sciences, Vanderbilt University, Nashville, TN, United States
| | - Logan A. Northcutt
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, United States
- Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
- United States Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States
| | - Jade S. Miller
- Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
- United States Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States
- Pharmacology Training Program, Department of Pharmacology, Vanderbilt University, Nashville, TN, United States
| | - Erik P. Beadle
- Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
- United States Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Julie A. Rhoades
- Program in Cancer Biology, Vanderbilt University, Nashville, TN, United States
- Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, United States
- United States Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, United States
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12
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Dawalibi A, Alosaimi AA, Mohammad KS. Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments. Int J Mol Sci 2024; 25:8163. [PMID: 39125732 PMCID: PMC11311339 DOI: 10.3390/ijms25158163] [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: 06/30/2024] [Revised: 07/15/2024] [Accepted: 07/19/2024] [Indexed: 08/12/2024] Open
Abstract
Bone metastases, a common and debilitating consequence of advanced cancers, involve a complex interplay between malignant cells and the bone microenvironment. Central to this interaction are interleukins (ILs), a group of cytokines with critical roles in immune modulation and inflammation. This review explores the dualistic nature of pro-inflammatory and anti-inflammatory interleukins in bone metastases, emphasizing their molecular mechanisms, pathological impacts, and therapeutic potential. Pro-inflammatory interleukins, such as IL-1, IL-6, and IL-8, have been identified as key drivers in promoting osteoclastogenesis, tumor proliferation, and angiogenesis. These cytokines create a favorable environment for cancer cell survival and bone degradation, contributing to the progression of metastatic lesions. Conversely, anti-inflammatory interleukins, including IL-4, IL-10, and IL-13, exhibit protective roles by modulating immune responses and inhibiting osteoclast activity. Understanding these opposing effects is crucial for developing targeted therapies aimed at disrupting the pathological processes in bone metastases. Key signaling pathways, including NF-κB, JAK/STAT, and MAPK, mediate the actions of these interleukins, influencing tumor cell survival, immune cell recruitment, and bone remodeling. Targeting these pathways presents promising therapeutic avenues. Current treatment strategies, such as the use of denosumab, tocilizumab, and emerging agents like bimekizumab and ANV419, highlight the potential of interleukin-targeted therapies in mitigating bone metastases. However, challenges such as therapeutic resistance, side effects, and long-term efficacy remain significant hurdles. This review also addresses the potential of interleukins as diagnostic and prognostic biomarkers, offering insights into patient stratification and personalized treatment approaches. Interleukins have multifaceted roles that depend on the context, including the environment, cell types, and cellular interactions. Despite substantial progress, gaps in research persist, particularly regarding the precise mechanisms by which interleukins influence the bone metastatic niche and their broader clinical implications. While not exhaustive, this overview underscores the critical roles of interleukins in bone metastases and highlights the need for continued research to fully elucidate their complex interactions and therapeutic potential. Addressing these gaps will be essential for advancing our understanding and treatment of bone metastases in cancer patients.
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Affiliation(s)
- Ahmad Dawalibi
- Department of Anatomy, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia;
| | - Amal Ahmed Alosaimi
- College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh 11432, Saudi Arabia;
| | - Khalid S. Mohammad
- Department of Anatomy, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia;
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13
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Yamato G, Tsumura Y, Muramatsu H, Shimada A, Imaizumi T, Tsukagoshi H, Kaburagi T, Shiba N, Yamada Y, Deguchi T, Kawai T, Terui K, Ito E, Watanabe K, Hayashi Y. Cytokine profiling in 128 patients with transient abnormal myelopoiesis: a report from the JPLSG TAM-10 trial. Blood Adv 2024; 8:3120-3129. [PMID: 38691583 PMCID: PMC11222942 DOI: 10.1182/bloodadvances.2023011628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 04/22/2024] [Accepted: 04/29/2024] [Indexed: 05/03/2024] Open
Abstract
ABSTRACT Transient abnormal myelopoiesis (TAM) occurs in 10% of neonates with Down syndrome (DS). Although most patients show spontaneous resolution of TAM, early death occurs in ∼20% of cases. Therefore, new biomarkers are needed to predict early death and determine therapeutic interventions. This study aimed to determine the association between clinical characteristics and cytokine levels in patients with TAM. A total of 128 patients with DS with TAM enrolled in the TAM-10 study conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group were included in this study. Five cytokine levels (interleukin-1b [IL-1b], IL-1 receptor agonist, IL-6, IL-8, and IL-13) were significantly higher in patients with early death than in those with nonearly death. Cumulative incidence rates (CIRs) of early death were significantly associated with high levels of the 5 cytokines. Based on unsupervised consensus clustering, patients were classified into 3 cytokine groups: hot-1 (n = 37), hot-2 (n = 42), and cold (n = 49). The CIR of early death was significantly different between the cytokine groups (hot-1/2, n = 79; cold, n = 49; hot-1/2 CIR, 16.5% [95% confidence interval (CI), 7.9-24.2]; cold CIR, 2.0% [95% CI, 0.0-5.9]; P = .013). Furthermore, cytokine groups (hot-1/2 vs cold) were independent poor prognostic factors in the multivariable analysis for early death (hazard ratio, 15.53; 95% CI, 1.434-168.3; P = .024). These results provide valuable information that cytokine level measurement was useful in predicting early death in patients with TAM and might help to determine the need for therapeutic interventions. This trial was registered at UMIN Clinical Trials Registry as #UMIN000005418.
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Affiliation(s)
- Genki Yamato
- Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Japan
- Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Yusuke Tsumura
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideki Muramatsu
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akira Shimada
- Department of Pediatrics, Jichi Medical University, Shimotsuke, Japan
| | - Takahiro Imaizumi
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Hiroyuki Tsukagoshi
- Department of Research Group, Gunma Prefectural Institute of Public Health and Environmental Sciences, Maebashi, Japan
| | - Taeko Kaburagi
- Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Japan
| | - Norio Shiba
- Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yoshiyuki Yamada
- Department of Allergy and Immunology, Gunma Children's Medical Center, Shibukawa, Japan
- Department of Pediatrics, Tokai University School of Medicine, Isehara, Japan
| | - Takao Deguchi
- Children’s Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Tomoko Kawai
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Kiminori Terui
- Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Etsuro Ito
- Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Kenichiro Watanabe
- Department of Hematology and Oncology, Shizuoka Children's Hospital, Shizuoka, Japan
| | - Yasuhide Hayashi
- Department of Hematology/Oncology, Gunma Children's Medical Center, Shibukawa, Japan
- Institute of Physiology and Medicine, Jobu University, Takasaki, Japan
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14
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Gallant JP, Hintz HM, Gunaratne GS, Breneman MT, Recchia EE, West JL, Ott KL, Heninger E, Jackson AE, Luo NY, Rosenkrans ZT, Hernandez R, Zhao SG, Lang JM, Meimetis L, Kosoff D, LeBeau AM. Mechanistic Characterization of Cancer-associated Fibroblast Depletion via an Antibody-Drug Conjugate Targeting Fibroblast Activation Protein. CANCER RESEARCH COMMUNICATIONS 2024; 4:1481-1494. [PMID: 38747612 PMCID: PMC11168342 DOI: 10.1158/2767-9764.crc-24-0248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/08/2024] [Accepted: 05/09/2024] [Indexed: 06/14/2024]
Abstract
Cancer-associated fibroblasts (CAF) are a prominent cell type within the tumor microenvironment (TME) where they are known to promote cancer cell growth and survival, angiogenesis, drug resistance, and immunosuppression. The transmembrane prolyl protease fibroblast activation protein (FAP) is expressed on the surface of highly protumorigenic CAFs found in the stroma of nearly every cancer of epithelial origin. The widespread expression of FAP has made it an attractive therapeutic target based on the underlying hypothesis that eliminating protumorigenic CAFs will disrupt the cross-talk between components of TME resulting in cancer cell death and immune infiltration. This hypothesis, however, has never been directly proven. To eliminate FAP-expressing CAFs, we developed an antibody-drug conjugate using our anti-FAP antibody, huB12, coupled to a monomethyl auristatin E (huB12-MMAE) payload. After determining that huB12 was an effective targeting vector, we found that huB12-MMAE potently eliminated FAP-expressing cells as monocultures in vitro and significantly prolonged survival in vivo using a xenograft engineered to overexpress FAP. We investigated the effects of selectively eliminating CAFs using a layered, open microfluidic cell coculture platform, known as the Stacks. Analysis of mRNA and protein expression found that treatment with huB12-MMAE resulted in the increased secretion of the proinflammatory cytokines IL6 and IL8 by CAFs and an associated increase in expression of proinflammatory genes in cancer cells. We also detected increased secretion of CSF1, a cytokine involved in myeloid recruitment and differentiation. Our findings suggest that the mechanism of FAP-targeted therapies is through effects on the immune microenvironment and antitumor immune response. SIGNIFICANCE The direct elimination of FAP-expressing CAFs disrupts the cross-talk with cancer cells leading to a proinflammatory response and alterations in the immune microenvironment and antitumor immune response.
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Affiliation(s)
- Joseph P. Gallant
- Molecular and Cellular Pharmacology Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Hallie M. Hintz
- Department of Pharmacology, University of Minnesota School of Medicine, Minneapolis, Minnesota
| | - Gihan S. Gunaratne
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Matthew T. Breneman
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Emma E. Recchia
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Jayden L. West
- Molecular and Cellular Pharmacology Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Kendahl L. Ott
- Molecular and Cellular Pharmacology Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Erika Heninger
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Abigail E. Jackson
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Natalie Y. Luo
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Zachary T. Rosenkrans
- Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Reinier Hernandez
- Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Shuang G. Zhao
- University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Joshua M. Lang
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Labros Meimetis
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - David Kosoff
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- William S Middleton Memorial Veterans’ Hospital, Madison, Wisconsin
| | - Aaron M. LeBeau
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
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15
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Galiana-Melendez F, Huot JR. The Impact of Non-bone Metastatic Cancer on Musculoskeletal Health. Curr Osteoporos Rep 2024; 22:318-329. [PMID: 38649653 DOI: 10.1007/s11914-024-00872-4] [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] [Accepted: 04/14/2024] [Indexed: 04/25/2024]
Abstract
PURPOSE OF REVIEW The purpose of this review is to discuss the musculoskeletal consequences of cancer, including those that occur in the absence of bone metastases. RECENT FINDINGS Cancer patients frequently develop cachexia, a debilitating condition reflected by weight loss and skeletal muscle wasting. The negative effects that tumors exert on bone health represents a growing interest amongst cachexia researchers. Recent clinical and pre-clinical evidence demonstrates cancer-induced bone loss, even in the absence of skeletal metastases. Together with muscle wasting, losses in bone demonstrates the impact of cancer on the musculoskeletal system. Identifying therapeutic targets that comprehensively protect musculoskeletal health is essential to improve the quality of life in cancer patients and survivors. IL-6, RANKL, PTHrP, sclerostin, and TGF-β superfamily members represent potential targets to counteract cachexia. However, more research is needed to determine the efficacy of these targets in protecting both skeletal muscle and bone.
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Affiliation(s)
| | - Joshua R Huot
- Department of Anatomy, Cell Biology & Physiology, Indianapolis, IN, 46202, USA.
- Indiana Center for Musculoskeletal Health, Indianapolis, IN, USA.
- Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Kinesiology, School of Health and Human Sciences, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.
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16
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Qiu Y, Zhang S, Man C, Gong D, Xu Y, Fan Y, Wang X, Zhang W. Advances on Senescence-associated secretory phenotype regulated by circular RNAs in tumors. Ageing Res Rev 2024; 97:102287. [PMID: 38570142 DOI: 10.1016/j.arr.2024.102287] [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: 02/26/2024] [Revised: 03/23/2024] [Accepted: 03/28/2024] [Indexed: 04/05/2024]
Abstract
The components that comprise the senescence-associated secretory phenotype (SASP) include growth factors, proteases, chemokines, cytokines, and bioactive lipids. It drives secondary aging and disrupts tissue homeostasis, ultimately leading to tissue repair and regeneration loss. It has a two-way regulatory effect on tumor cells, resisting cancer occurrence and promoting its progression. A category of single-stranded circular non-coding RNA molecules known as circular RNAs (circRNAs) carries out a series of cellular activities, including sequestering miRNAs and modulating gene editing and expression. Research has demonstrated that a large number of circRNAs exhibit aberrant expression in pathological settings, and play a part in the onset and progress of cancer via modulating SASP factors. However, the research related to SASP and circRNAs in tumors is still in its infancy at this stage. This review centers on the bidirectional modulation of SASP and the role of circRNAs in regulating SASP factors across different types of tumors. The aim is to present novel perspectives for the diagnosis and therapeutic management of malignancies.
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Affiliation(s)
- Yue Qiu
- Cancer Institute, Affiliated People's Hospital of Jiangsu University, No 8, Dianli Road, Zhenjiang, Jiangsu 212002, People's Republic of China
| | - Shiqi Zhang
- Department of Gastroenterology, Affiliated Suqian First People's Hospital of Nanjing Medical University, No 120, Suzhi Road, Suqian, Jiangsu 223812, People's Republic of China
| | - Changfeng Man
- Cancer Institute, Affiliated People's Hospital of Jiangsu University, No 8, Dianli Road, Zhenjiang, Jiangsu 212002, People's Republic of China
| | - Dandan Gong
- Cancer Institute, Affiliated People's Hospital of Jiangsu University, No 8, Dianli Road, Zhenjiang, Jiangsu 212002, People's Republic of China
| | - Ying Xu
- Laboratory Center, Jiangsu University Affiliated People's Hospital, Zhenjiang, Jiangsu, People's Republic of China
| | - Yu Fan
- Cancer Institute, Affiliated People's Hospital of Jiangsu University, No 8, Dianli Road, Zhenjiang, Jiangsu 212002, People's Republic of China.
| | - Xiaoyan Wang
- Department of Gastroenterology, Affiliated Suqian First People's Hospital of Nanjing Medical University, No 120, Suzhi Road, Suqian, Jiangsu 223812, People's Republic of China.
| | - Wenbo Zhang
- General Surgery Department, Jiangsu University Affiliated People's Hospital, Zhenjiang, Jiangsu, People's Republic of China.
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17
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Kumar V, Naqvi SM, Verbruggen A, McEvoy E, McNamara LM. A mechanobiological model of bone metastasis reveals that mechanical stimulation inhibits the pro-osteolytic effects of breast cancer cells. Cell Rep 2024; 43:114043. [PMID: 38642336 DOI: 10.1016/j.celrep.2024.114043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 12/01/2023] [Accepted: 03/19/2024] [Indexed: 04/22/2024] Open
Abstract
Bone is highly susceptible to cancer metastasis, and both tumor and bone cells enable tumor invasion through a "vicious cycle" of biochemical signaling. Tumor metastasis into bone also alters biophysical cues to both tumor and bone cells, which are highly sensitive to their mechanical environment. However, the mechanobiological feedback between these cells that perpetuate this cycle has not been studied. Here, we develop highly advanced in vitro and computational models to provide an advanced understanding of how tumor growth is regulated by the synergistic influence of tumor-bone cell signaling and mechanobiological cues. In particular, we develop a multicellular healthy and metastatic bone model that can account for physiological mechanical signals within a custom bioreactor. These models successfully recapitulated mineralization, mechanobiological responses, osteolysis, and metastatic activity. Ultimately, we demonstrate that mechanical stimulus provided protective effects against tumor-induced osteolysis, confirming the importance of mechanobiological factors in bone metastasis development.
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Affiliation(s)
- Vatsal Kumar
- Mechanobiology and Medical Device Research Group (MMDRG), Biomedical Engineering, College of Science and Engineering, University of Galway, H91 HX31 Galway, Ireland
| | - Syeda M Naqvi
- Mechanobiology and Medical Device Research Group (MMDRG), Biomedical Engineering, College of Science and Engineering, University of Galway, H91 HX31 Galway, Ireland
| | - Anneke Verbruggen
- Mechanobiology and Medical Device Research Group (MMDRG), Biomedical Engineering, College of Science and Engineering, University of Galway, H91 HX31 Galway, Ireland
| | - Eoin McEvoy
- Biomedical Engineering, College of Science and Engineering, University of Galway, H91 HX31 Galway, Ireland
| | - Laoise M McNamara
- Mechanobiology and Medical Device Research Group (MMDRG), Biomedical Engineering, College of Science and Engineering, University of Galway, H91 HX31 Galway, Ireland.
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18
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Arakil N, Akhund SA, Elaasser B, Mohammad KS. Intersecting Paths: Unraveling the Complex Journey of Cancer to Bone Metastasis. Biomedicines 2024; 12:1075. [PMID: 38791037 PMCID: PMC11117796 DOI: 10.3390/biomedicines12051075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 04/27/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
The phenomenon of bone metastases presents a significant challenge within the context of advanced cancer treatments, particularly pertaining to breast, prostate, and lung cancers. These metastatic occurrences stem from the dissemination of cancerous cells into the bone, thereby interrupting the equilibrium between osteoblasts and osteoclasts. Such disruption results in skeletal complications, adversely affecting patient morbidity and quality of life. This review discusses the intricate interplay between cancer cells and the bone microenvironment, positing the bone not merely as a passive recipient of metastatic cells but as an active contributor to cancer progression through its distinctive biochemical and cellular makeup. A thorough examination of bone structure and the dynamics of bone remodeling is undertaken, elucidating how metastatic cancer cells exploit these processes. This review explores the genetic and molecular pathways that underpin the onset and development of bone metastases. Particular emphasis is placed on the roles of cytokines and growth factors in facilitating osteoclastogenesis and influencing osteoblast activity. Additionally, this paper offers a meticulous critique of current diagnostic methodologies, ranging from conventional radiography to advanced molecular imaging techniques, and discusses the implications of a nuanced understanding of bone metastasis biology for therapeutic intervention. This includes the development of targeted therapies and strategies for managing bone pain and other skeletal-related events. Moreover, this review underscores the imperative of ongoing research efforts aimed at identifying novel therapeutic targets and refining management approaches for bone metastases. It advocates for a multidisciplinary strategy that integrates advancements in medical oncology and radiology with insights derived from molecular biology and genetics, to enhance prognostic outcomes and the quality of life for patients afflicted by this debilitating condition. In summary, bone metastases constitute a complex issue that demands a comprehensive and informed approach to treatment. This article contributes to the ongoing discourse by consolidating existing knowledge and identifying avenues for future investigation, with the overarching objective of ameliorating patient care in the domain of oncology.
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Affiliation(s)
| | | | | | - Khalid S. Mohammad
- Department of Anatomy, College of Medicine, Alfaisal University, Riyadh 1153, Saudi Arabia; (N.A.); (S.A.A.); (B.E.)
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19
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Maiorano BA, Schinzari G, Carbone C, Piro G, Rossi E, Di Maio M, Di Giacomo A, Maiello E. Prognostic role of circulating cytokines and inflammation indexes for avelumab maintenance in metastatic urothelial carcinoma. Front Immunol 2024; 15:1401214. [PMID: 38799450 PMCID: PMC11116647 DOI: 10.3389/fimmu.2024.1401214] [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: 03/14/2024] [Accepted: 04/18/2024] [Indexed: 05/29/2024] Open
Abstract
Background Avelumab maintenance after first-line platinum-based chemotherapy represents a cornerstone for the treatment of metastatic urothelial carcinoma (mUC). However, identifying prognostic biomarkers is paramount for optimizing patients' benefits while minimizing toxicity. Cytokines represent circulating mediators of the complex interaction between cancer, the immune system, and inflammation. Inflammation, a hallmark of cancer, can be expressed by circulating factors. In different tumor subtypes, peripheral blood biomarkers, such as circulating cytokines, and systemic inflammatory indexes, have been addressed as potential prognostic factors for immune checkpoint inhibitors. However, their role in mUC still needs to be determined. Methods Between February 2021 and April 2023, we prospectively collected plasma cytokines and inflammation indexes in 28 patients with mUC before starting avelumab as first-line maintenance. The primary endpoint was the relationship between baseline cytokines and inflammatory indexes with the clinical benefit (CB), defined as the number of Responders. Secondary endpoints included the correlation of baseline cytokines and inflammatory indexes with progression-free survival (PFS), overall survival (OS), and the number and grade of immune-related adverse events. Results High pre-treatment levels of interferon (IFN)-γ and interleukin (IL)-2, and low levels of IL-6, IL-8, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and systemic-inflammation index (SII) were associated with clinical benefit and longer survival. In the multivariate analysis, low IL-8, NLR, and SII levels maintained a positive prognostic value for OS. Conclusion Our data suggest that, in mUC patients receiving avelumab, pre-treatment levels of plasma cytokines and inflammatory indexes may serve as potential prognostic biomarkers for response and efficacy. In particular, patients with signs of pre-therapeutic inflammation showed a significantly lower response and survival to avelumab. On the contrary, low systemic inflammation and high levels of cytokines characterized responders and longer survivors.
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Affiliation(s)
- Brigida Anna Maiorano
- Oncology Unit, IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy
- Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy
| | - Giovanni Schinzari
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Carmine Carbone
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Geny Piro
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Ernesto Rossi
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | | | | | - Evaristo Maiello
- Oncology Unit, IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy
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20
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Huang W, Liu W, Yu T, Zhang Z, Zhai L, Huang P, Lu Y. Effect of anti-COVID-19 drugs on patients with cancer. Eur J Med Chem 2024; 268:116214. [PMID: 38367490 DOI: 10.1016/j.ejmech.2024.116214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 01/11/2024] [Accepted: 02/01/2024] [Indexed: 02/19/2024]
Abstract
The clinical treatment of patients with cancer who are also diagnosed with coronavirus disease (COVID-19) has been a challenging issue since the outbreak of COVID-19. Therefore, it is crucial to understand the effects of commonly used drugs for treating COVID-19 in patients with cancer. Hence, this review aims to provide a reference for the clinical treatment of patients with cancer to minimize the losses caused by the COVID-19 pandemic. In this study, we also focused on the relationship between COVID-19, commonly used drugs for treating COVID-19, and cancer. We specifically investigated the effect of these drugs on tumor cell proliferation, migration, invasion, and apoptosis. The potential mechanisms of action of these drugs were discussed and evaluated. We found that most of these drugs showed inhibitory effects on tumors, and only in a few cases had cancer-promoting effects. Furthermore, inappropriate usage of these drugs may lead to irreversible kidney and heart damage. Finally, we have clarified the use of different drugs, which can provide useful guidance for the clinical treatment of cancer patients diagnosed with COVID-19.
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Affiliation(s)
- Weicai Huang
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Wenyu Liu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Tingting Yu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Zhaoyang Zhang
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Lingyun Zhai
- Gynecology Department, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
| | - Panpan Huang
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China.
| | - Yao Lu
- School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi 341000, China.
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21
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Erdogan S, Serttas R, Dibirdik I, Turkekul K. Multifaceted impact of adipose conditioned media: Obesity-driven promotion of prostate cancer and cancer stem cell dynamics. Cell Biochem Funct 2024; 42:e3979. [PMID: 38481004 DOI: 10.1002/cbf.3979] [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: 10/04/2023] [Revised: 03/01/2024] [Accepted: 03/04/2024] [Indexed: 03/22/2024]
Abstract
Obesity is an established risk factor for the development and progression of prostate cancer (PC). This study used adipose conditioned media (ACM) from differentiated adipocytes to assess its effect on PC development and aggressiveness. Due to limited research on ACM's impact on isolated PC stem cells (PCSCs), we also examined CD44+ PCSCs. ACM notably boosted interleukin-1β (IL-1β), IL-6, and IL-8 production in normal prostate epithelial cells and LNCaP cells. It also increased IL-6 and IL-8 production in PC3 and CD44+ LNCaP cells, and IL-1β and IL-6 production in CD44+ PC3 cells. This indicates that ACM induces the production of inflammatory cytokines in both cancer and prostate epithelial cells. Furthermore, ACM promoted proliferation in androgen receptor (AR)-negative PC3 cells, CD44+ PC3 PCSCs, and nonmalignant RWPE cells, without affecting AR-positive LNCaP cells. In addition, ACM-enhanced invasion and migration potential in both PC3 and CD44+ PC3 cells. Western blot analysis indicated the involvement of NF-κB and AKT pathways in ACM-induced proliferation in PC3 cells and NF-κB in PCSCs. In ACM-treated PC3 cells, E-cadherin was downregulated, while N-cadherin, Snail, vimentin, fibronectin, and Twist were upregulated, suggesting ACM-induced invasion via classical epithelial-to-mesenchymal transition (EMT) pathways. In response to ACM, PCSCs exhibited increased expression of E-cadherin, Snail, and vimentin, which are partial EMT markers promoting stemness and resistance to apoptosis. In addition, increased expressions of Nanog, Oct3/4, survivin, and Bcl-2 were observed. Although the molecules we studied have diverse effects on cellular regulation, our data emphasize obesity's multifaceted role in promoting and aggressing PC, notably affecting PCSC populations.
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Affiliation(s)
- Suat Erdogan
- Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Türkiye
| | - Riza Serttas
- Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Türkiye
| | - Ilker Dibirdik
- Department of Medical Biochemistry, School of Medicine, Trakya University, Balkan Campus, Edirne, Türkiye
| | - Kader Turkekul
- Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Türkiye
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22
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Adachi T, Goda H, Shinriki S, Tokuzen N, Kuribayashi N, Hino S, Nakashiro KI, Uchida D. Prognostic Significance of Serum Interleukin-6 Levels in Oral Squamous Cell Carcinoma. Cureus 2024; 16:e54439. [PMID: 38510850 PMCID: PMC10951754 DOI: 10.7759/cureus.54439] [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] [Accepted: 02/19/2024] [Indexed: 03/22/2024] Open
Abstract
Introduction The prognosis of oral squamous cell carcinoma (OSCC) is often poor despite standard treatments. Additionally, no useful prognostic markers are available. Therefore, we aimed to investigate the relationship between serum Interleukin-6 (IL-6) levels and prognosis and explore its local and systemic effects in patients with OSCC. Methods Ninety-five new cases of OSCC were included, and the prognosis was compared between high and low serum IL-6 groups. The localization of IL-6 in OSCC tissues was examined. Furthermore, a comprehensive gene expression analysis was performed in OSCC tissues and compared between the two groups. Results A significant difference in overall survival and disease-free survival was observed. Furthermore, a substantial expression of IL-6 was localized in the stroma. Comprehensive gene expression analysis of tumor localization showed increased expression of genes related to oxidoreductase and lipid metabolism in the primary tissues of the group with high serum IL-6 levels. Regarding the correlation between blood tests and serum IL-6 levels, a strong positive correlation was observed between inflammatory responses and nutritional factors. Conclusion These results suggest that serum IL-6 may be a prognostic factor for metabolic abnormalities in patients with OSCC and that aggressive nutritional interventions may contribute to prognosis.
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Affiliation(s)
- Tomoko Adachi
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, JPN
| | - Hiroyuki Goda
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, JPN
| | - Satoru Shinriki
- Department of Molecular Laboratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, JPN
| | - Norihiko Tokuzen
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, JPN
| | - Nobuyuki Kuribayashi
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, JPN
| | - Satoshi Hino
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, JPN
| | - Koh-Ichi Nakashiro
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, JPN
| | - Daisuke Uchida
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Ehime, JPN
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23
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Yang Y, Jin C, Yeo A, Jin B. Multiple Factors Determine the Oncolytic or Carcinogenic Effects of TLRs Activation in Cancer. J Immunol Res 2024; 2024. [DOI: 10.1155/2024/1111551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 12/13/2023] [Indexed: 01/05/2025] Open
Abstract
Toll‐like receptors (TLRs) belong to a germline‐encoded protein family. These are pattern recognition receptors. They sense pathogen‐associated molecular patterns (PAMPs). When this occurs, activation of the NF‐ĸB pathway follows. This triggers the innate immune response of the host. The consequent inflammatory cytokine response usually contributes to the elimination of the pathogen. Activation of TLRs also induces an adaptive immune response by a cross‐prime mechanism. This mechanism is employed in cancer immunotherapy. Using TLR ligands as adjuvants induces upregulation of costimulatory signals which in turn activates a cytotoxic leukocyte response against cancer cells. However, TLRs are also overexpressed in human cancer cells resulting in increased cell proliferation, migration, invasion, and angiogenesis. An intracellular adaptor, myeloid differentiation factor 88 (MyD88) probably mediates this process. MyD88 is intimately involved with all TLRs except TLR3. One consequence of the interaction between a TLR and MyD88 is activation of NF‐ĸB. In this context of a variety of proinflammtory cytokines being produced, chronic inflammation may result. Inflammation is an important protective mechanism. However, chronic inflammation is also involved in carcinogenesis. Activation of NF‐ĸB inhibits apoptosis and under certain circumstances, tumor cell survival. In this review, the potential therapeutic value of TLRs in immunotherapy and its role in oncogenesis are explored. The emerging use of artificial intelligence is mentioned.
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24
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Hu R, Ling X, Yang T, Zhang J, Gu X, Li F, Chen H, Wen Y, Li Z, Zou Y, Du Y. Cytokine levels in patients with non-M3 myeloid leukemia are key indicators of how well the disease responds to chemotherapy. Clin Exp Med 2023; 23:4623-4632. [PMID: 37925379 DOI: 10.1007/s10238-023-01242-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 10/26/2023] [Indexed: 11/06/2023]
Abstract
Acute myeloid leukemia (AML) is a malignant hematological neoplastic disease. Autocrine or paracrine cytokines released by leukemic cells regulate the proliferation of AML cells. It is uncertain whether cytokines can indicate whether patients with AML are in remission with chemotherapy. The goal of this study was to evaluate the levels of Th1/Th2/Th17 cytokines in AML patients before and after chemotherapy to determine whether the cytokine levels could predict disease remission after chemotherapy. It was found that the levels of IL-5, IL-6, IL-8, IL-10, TNF-α, TNF-β, IL-17F, and IL-22 were significantly increased at the time of AML diagnosis in patients who achieved remission after two chemotherapy treatments (P < 0.05). After chemotherapy, the cytokine levels were reduced in patients with remission, while the levels of IL-6 and IL-8 were raised in patients without remission (P < 0.05). A comparison of cytokine levels before and after chemotherapy in patients who achieved remission showed areas under the curve (AUCs) of 0.69 for both IL-6 and IL-8. In addition, a comparison of the remission and non-remission groups after chemotherapy showed an AUC of 0.77 for IL-6. We then calculated the cutoff value using receiver operating characteristic curves. Values of IL-6 < 9.99 and IL-8 < 8.46 at the time of diagnosis were predictive of chemotherapy success and remission, while IL-6 > 14.89 at diagnosis suggested that chemotherapy would not be successful and remission would not be achieved. Multifactorial analysis showed that age, Neu, IL-6, and IL-8 were independent risk factors for AML prognosis, and IL-6 (OR = 5.48, P = 0.0038) was superior to age (OR = 3.36, P = 0.0379), Neu (OR = 0.28, P = 0.0308), IL-8 (OR = 0.0421, P = 0.0421). In conclusion, IL-6 levels were found to be predictive of the likelihood of remission.
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Affiliation(s)
- Rui Hu
- Department of Hematology, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
- Yunnan Province Clinical Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China
- Yunnan Blood Disease Hospital, The First People's Hospital of Yunnan Province, Kunming, China
- Yunnan Province Clinical Research Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China
| | - Xiaosui Ling
- Department of Hematology, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
- Yunnan Province Clinical Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China
- Yunnan Blood Disease Hospital, The First People's Hospital of Yunnan Province, Kunming, China
- Yunnan Province Clinical Research Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China
| | - Tonghua Yang
- Department of Hematology, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
- Yunnan Province Clinical Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China
- Yunnan Blood Disease Hospital, The First People's Hospital of Yunnan Province, Kunming, China
- Yunnan Province Clinical Research Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China
| | - Jinping Zhang
- Department of Hematology, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
- Yunnan Province Clinical Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China
- Yunnan Blood Disease Hospital, The First People's Hospital of Yunnan Province, Kunming, China
- Yunnan Province Clinical Research Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China
| | - Xuezhong Gu
- Department of Hematology, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
- Yunnan Province Clinical Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China
- Yunnan Blood Disease Hospital, The First People's Hospital of Yunnan Province, Kunming, China
- Yunnan Province Clinical Research Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China
| | - Fan Li
- Department of Hematology, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
- Yunnan Province Clinical Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China
- Yunnan Blood Disease Hospital, The First People's Hospital of Yunnan Province, Kunming, China
- Yunnan Province Clinical Research Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China
| | - Heng Chen
- The Second Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yan Wen
- Department of Hematology, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
- Yunnan Province Clinical Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China
- Yunnan Blood Disease Hospital, The First People's Hospital of Yunnan Province, Kunming, China
- Yunnan Province Clinical Research Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China
| | - Zengzheng Li
- Department of Hematology, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.
- Yunnan Province Clinical Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China.
- Yunnan Blood Disease Hospital, The First People's Hospital of Yunnan Province, Kunming, China.
- Yunnan Province Clinical Research Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China.
| | - Yunlian Zou
- Department of Hematology, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.
- Yunnan Province Clinical Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China.
- Yunnan Blood Disease Hospital, The First People's Hospital of Yunnan Province, Kunming, China.
- Yunnan Province Clinical Research Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China.
| | - Yunyun Du
- Department of Hematology, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.
- Yunnan Province Clinical Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China.
- Yunnan Blood Disease Hospital, The First People's Hospital of Yunnan Province, Kunming, China.
- Yunnan Province Clinical Research Center for Hematologic Disease, The First People's Hospital of Yunnan Province, Kunming, China.
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25
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Soler MF, Abaurrea A, Azcoaga P, Araujo AM, Caffarel MM. New perspectives in cancer immunotherapy: targeting IL-6 cytokine family. J Immunother Cancer 2023; 11:e007530. [PMID: 37945321 PMCID: PMC10649711 DOI: 10.1136/jitc-2023-007530] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2023] [Indexed: 11/12/2023] Open
Abstract
Chronic inflammation has been recognized as a canonical cancer hallmark. It is orchestrated by cytokines, which are master regulators of the tumor microenvironment (TME) as they represent the main communication bridge between cancer cells, the tumor stroma, and the immune system. Interleukin (IL)-6 represents a keystone cytokine in the link between inflammation and cancer. Many cytokines from the IL-6 family, which includes IL-6, oncostatin M, leukemia inhibitory factor, IL-11, IL-27, IL-31, ciliary neurotrophic factor, cardiotrophin 1, and cardiotrophin-like cytokine factor 1, have been shown to elicit tumor-promoting roles by modulating the TME, making them attractive therapeutic targets for cancer treatment.The development of immune checkpoint blockade (ICB) immunotherapies has radically changed the outcome of some cancers including melanoma, lung, and renal, although not without hurdles. However, ICB shows limited efficacy in other solid tumors. Recent reports support that chronic inflammation and IL-6 cytokine signaling are involved in resistance to immunotherapy. This review summarizes the available preclinical and clinical data regarding the implication of IL-6-related cytokines in regulating the immune TME and the response to ICB. Moreover, the potential clinical benefit of combining ICB with therapies targeting IL-6 cytokine members for cancer treatment is discussed.
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Affiliation(s)
- Maria Florencia Soler
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
| | - Andrea Abaurrea
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
| | - Peio Azcoaga
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
| | - Angela M Araujo
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
| | - Maria M Caffarel
- Biogipuzkoa (previously known as Biodonostia) Health Research Institute, Donostia-San Sebastian, Spain
- Ikerbasque Basque Foundation for Science, Bilbao, Spain
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26
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Nenu I, Toadere TM, Topor I, Țichindeleanu A, Bondor DA, Trella ȘE, Sparchez Z, Filip GA. Interleukin-6 in Hepatocellular Carcinoma: A Dualistic Point of View. Biomedicines 2023; 11:2623. [PMID: 37892997 PMCID: PMC10603956 DOI: 10.3390/biomedicines11102623] [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: 08/23/2023] [Revised: 09/14/2023] [Accepted: 09/21/2023] [Indexed: 10/29/2023] Open
Abstract
Hepatocellular Carcinoma (HCC) is a pressing health concern, demanding a deep understanding of various mediators' roles in its development for therapeutic progress. Notably, interleukin-6 (IL-6) has taken center stage in investigations due to its intricate and context-dependent functions. This review delves into the dual nature of IL-6 in HCC, exploring its seemingly contradictory roles as both a promoter and an inhibitor of disease progression. We dissect the pro-tumorigenic effects of IL-6, including its impact on tumor growth, angiogenesis, and metastasis. Concurrently, we examine its anti-tumorigenic attributes, such as its role in immune response activation, cellular senescence induction, and tumor surveillance. Through a comprehensive exploration of the intricate interactions between IL-6 and the tumor microenvironment, this review highlights the need for a nuanced comprehension of IL-6 signaling in HCC. It underscores the importance of tailored therapeutic strategies that consider the dynamic stages and diverse surroundings within the tumor microenvironment. Future research directions aimed at unraveling the multifaceted mechanisms of IL-6 in HCC hold promise for developing more effective treatment strategies and improving patient outcomes.
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Affiliation(s)
- Iuliana Nenu
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
- Department of Gastroenterology, “Prof. Dr. O. Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania;
| | - Teodora Maria Toadere
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Ioan Topor
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Andra Țichindeleanu
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Daniela Andreea Bondor
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Șerban Ellias Trella
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
| | - Zeno Sparchez
- Department of Gastroenterology, “Prof. Dr. O. Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania;
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Gabriela Adriana Filip
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (I.N.); (T.M.T.); (A.Ț.); (D.A.B.); (Ș.E.T.); (G.A.F.)
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27
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Mubtasim N, Gollahon L. Characterizing 3T3-L1 MBX Adipocyte Cell Differentiation Maintained with Fatty Acids as an In Vitro Model to Study the Effects of Obesity. Life (Basel) 2023; 13:1712. [PMID: 37629569 PMCID: PMC10455818 DOI: 10.3390/life13081712] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 07/31/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023] Open
Abstract
The increasing prevalence of obesity has prompted intensive research into understanding its role in pathogenesis and designing appropriate treatments. To determine the signals generated from the interaction of fat cells with a target organ, a reliable white adipocyte model in vitro is needed. Differentiated fibroblasts are the most extensively studied using in vitro cell models of white adipocytes. However, it can be argued that differentiated fibroblasts minimally recapitulate the consequences of obesity. Here, we describe 3T3-L1 MBX cells as a culture model for studying obese adipocytes and their effects. Differentiation of 3T3-L1 MBX cells was at first optimized and then maintained in the presence of fatty acids cocktail combination to induce the obese condition. Lipid accumulation and adipokine secretion profiles were analyzed. Results showed that fatty acid-maintained, differentiated 3T3-L1 MBX cells had significantly greater accumulation of lipids and significant changes in the adipokine secretions in comparison to differentiated 3T3-L1 MBX cells maintained in medium without fatty acids. To elucidate the molecular changes associated with adipogenesis and lipid accumulation profile of 3T3-L1 MBX cells, we have also explored the expression of some of the regulatory proteins related to the development and maintenance of adipocytes from the preadipocyte lineage.
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Affiliation(s)
| | - Lauren Gollahon
- Department of Biological Sciences, Texas Tech University, 2500 Broadway, Lubbock, TX 79409, USA;
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28
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Zhou Y, Yuan R, Cone AS, Shifflett KW, Arias GF, Peng A, Chambers MG, McNamara RP, Willcox S, Landis JT, Pan Y, Griffith J, Dittmer DP. Large-scale heparin-based bind-and-elute chromatography identifies two biologically distinct populations of extracellular vesicles. J Extracell Vesicles 2023; 12:e12327. [PMID: 37272197 PMCID: PMC10240191 DOI: 10.1002/jev2.12327] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 04/10/2023] [Accepted: 04/20/2023] [Indexed: 06/06/2023] Open
Abstract
Purifying extracellular vesicles (EVs) has been challenging because EVs are heterogeneous in cargo yet share similar sizes and densities. Most surface marker-based affinity separation methods are limited to research or diagnostic scales. We report that heparin chromatography can separate purified EVs into two distinct subpopulations as ascertained by MS/MS: a non-heparin-binding (NHB) fraction that contains classical EV markers such as tetraspanins and a heparin-binding (HB) fraction enriched in fibronectins and histones. Both fractions were similarly fusogenic but induced different transcriptional responses in endothelial cells. While EVs that were purified by conventional, non-affinity methods alone induced ERK1/2 phosphorylation and Ki67, the NHB fraction did not. This result suggests heparin chromatography as an additional novel fractionation step that is inherently scalable, does not lead to loss of material, and separates inflammatory and pyrogenic EVs from unreactive EVs, which will improve clinical applications.
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Affiliation(s)
- Yijun Zhou
- Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Microbiology and ImmunologyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Runjie Yuan
- Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Microbiology and ImmunologyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Allaura S. Cone
- Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Microbiology and ImmunologyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Kyle W. Shifflett
- Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Microbiology and ImmunologyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Gabriel F. Arias
- Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Biochemistry and BiophysicsThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Alice Peng
- Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Microbiology and ImmunologyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Meredith G. Chambers
- Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Microbiology and ImmunologyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Ryan P. McNamara
- Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Microbiology and ImmunologyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Smaranda Willcox
- Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Justin T. Landis
- Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Microbiology and ImmunologyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Yue Pan
- Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of BiostatisticsThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Jack Griffith
- Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Biochemistry and BiophysicsThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Dirk P. Dittmer
- Lineberger Comprehensive Cancer CenterThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
- Department of Microbiology and ImmunologyThe University of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
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29
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Allegra A, Murdaca G, Mirabile G, Gangemi S. Redox Signaling Modulates Activity of Immune Checkpoint Inhibitors in Cancer Patients. Biomedicines 2023; 11:1325. [PMID: 37238995 PMCID: PMC10215686 DOI: 10.3390/biomedicines11051325] [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: 04/06/2023] [Revised: 04/23/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
Although immunotherapy is already a staple of cancer care, many patients may not benefit from these cutting-edge treatments. A crucial field of research now focuses on figuring out how to improve treatment efficacy and assess the resistance mechanisms underlying this uneven response. For a good response, immune-based treatments, in particular immune checkpoint inhibitors, rely on a strong infiltration of T cells into the tumour microenvironment. The severe metabolic environment that immune cells must endure can drastically reduce effector activity. These immune dysregulation-related tumour-mediated perturbations include oxidative stress, which can encourage lipid peroxidation, ER stress, and T regulatory cells dysfunction. In this review, we have made an effort to characterize the status of immunological checkpoints, the degree of oxidative stress, and the part that latter plays in determining the therapeutic impact of immunological check point inhibitors in different neoplastic diseases. In the second section of the review, we will make an effort to assess new therapeutic possibilities that, by affecting redox signalling, may modify the effectiveness of immunological treatment.
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Affiliation(s)
- Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy;
| | - Giuseppe Murdaca
- Department of Internal Medicine, Ospedale Policlinico San Martino IRCCS, University of Genova, Viale Benedetto XV, n. 6, 16132 Genova, Italy
| | - Giuseppe Mirabile
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, 98125 Messina, Italy;
| | - Sebastiano Gangemi
- Allergy and Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
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Landini L, Marini M, Souza Monteiro de Araujo D, Romitelli A, Montini M, Albanese V, Titiz M, Innocenti A, Bianchini F, Geppetti P, Nassini R, De Logu F. Schwann Cell Insulin-like Growth Factor Receptor Type-1 Mediates Metastatic Bone Cancer Pain in Mice. Brain Behav Immun 2023; 110:348-364. [PMID: 36940752 DOI: 10.1016/j.bbi.2023.03.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/27/2023] [Accepted: 03/16/2023] [Indexed: 03/23/2023] Open
Abstract
Insulin growth factor-1 (IGF-1), an osteoclast-dependent osteolysis biomarker, contributes to metastatic bone cancer pain (MBCP), but the underlying mechanism is poorly understood. In mice, the femur metastasis caused by intramammary inoculation of breast cancer cells resulted in IGF-1 increase in femur and sciatic nerve, and IGF-1-dependent stimulus/non-stimulus-evoked pain-like behaviors. Adeno-associated virus-based shRNA selective silencing of IGF-1 receptor (IGF-1R) in Schwann cells, but not in dorsal root ganglion (DRG) neurons, attenuated pain-like behaviors. Intraplantar IGF-1 evoked acute nociception and mechanical/cold allodynia, which were reduced by selective IGF-1R silencing in DRG neurons and Schwann cells, respectively. Schwann cell IGF-1R signaling promoted an endothelial nitric oxide synthase-mediated transient receptor potential ankyrin 1 (TRPA1) activation and release of reactive oxygen species that, via macrophage-colony stimulating factor-dependent endoneurial macrophage expansion, sustained pain-like behaviors. Osteoclast derived IGF-1 initiates a Schwann cell-dependent neuroinflammatory response that sustains a proalgesic pathway that provides new options for MBCP treatment.
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Affiliation(s)
- Lorenzo Landini
- Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, 50139, Italy
| | - Matilde Marini
- Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, 50139, Italy
| | | | - Antonia Romitelli
- Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, 50139, Italy
| | - Marco Montini
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Medical Genetics Unit, University of Florence, 50141, Florence, Italy
| | - Valentina Albanese
- Department of Environmental and Prevention Sciences - DEPS, University of Ferrara, Ferrara, 44121, Italy
| | - Mustafa Titiz
- Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, 50139, Italy
| | - Alessandro Innocenti
- Plastic and Reconstructive Microsurgery - Careggi University Hospital, Florence, 50139, Italy
| | - Francesca Bianchini
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Section of Experimental Pathology and Oncology, University of Florence, 50141, Florence, Italy
| | - Pierangelo Geppetti
- Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, 50139, Italy
| | - Romina Nassini
- Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, 50139, Italy.
| | - Francesco De Logu
- Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, 50139, Italy
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Imai T, Nakamura K, Morita S, Hasegawa K, Goto T, Katori Y, Asada Y. Preoperative serum interleukin-6 level in head and neck cancer reflects systemic inflammatory response and is a predictor of postoperative prognosis. Jpn J Clin Oncol 2023; 53:230-236. [PMID: 36484303 DOI: 10.1093/jjco/hyac185] [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: 06/14/2022] [Accepted: 11/09/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The outcome of head and neck cancer has improved in recent years but survival is not yet satisfactory. Interleukin (IL)-6 is a representative inflammatory cytokine and inducer of systemic inflammatory response. It is not known whether preoperative serum level of IL-6 is a prognostic factor in head and neck cancer surgery. METHODS We studied 181 consecutive patients who underwent head and neck surgery with free tissue transfer reconstruction (HNS-FTTR) between September 2016 and December 2020. Whether preoperative serum IL-6 level was a prognostic risk factor was retrospectively investigated by univariate and multivariate analyses. We also investigated the association between preoperative IL-6 level and representative systemic inflammatory response markers. RESULTS The preoperative IL-6 ≥ 8 pg/mL group had a significantly worse prognosis than the preoperative IL-6 < 8 pg/mL group (overall survival [OS]: hazard ratio [HR] 3.098, P = 0.0006; disease-specific survival [DSS]: HR 3.335, P = 0.0008). In multivariate analysis, IL-6 ≥ 8 pg/mL and age ≥ 70 years were independent poor prognostic factors for OS (HR 1.860, P = 0.0435 and HR 1.883, P = 0.0233, respectively). The only independent poor prognostic factor for DSS was IL-6 ≥ 8 pg/mL (HR 2.052, P = 0.0329). Serum albumin was significantly lower and serum C-reactive protein and neutrophil-to-lymphocyte ratio were significantly higher in the IL-6 ≥ 8 pg/mL group than in the IL-6 < 8 pg/mL group (all P < 0.0001). CONCLUSIONS Preoperative serum IL-6 level is an independent poor prognostic factor for both OS and DSS after HNS-FTTR, reflecting the degree of preoperative systemic inflammatory response.
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Affiliation(s)
- Takayuki Imai
- Department of Head and Neck Surgery, Miyagi Cancer Center, Natori, Miyagi, Japan
| | - Kazuki Nakamura
- Department of Head and Neck Surgery, Miyagi Cancer Center, Natori, Miyagi, Japan.,Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Sinkichi Morita
- Department of Head and Neck Surgery, Miyagi Cancer Center, Natori, Miyagi, Japan
| | - Kohsei Hasegawa
- Department of Head and Neck Surgery, Miyagi Cancer Center, Natori, Miyagi, Japan
| | - Takahiro Goto
- Department of Plastic and Reconstructive Surgery, Miyagi Cancer Center, Natori, Miyagi, Japan
| | - Yukio Katori
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yukinori Asada
- Department of Head and Neck Surgery, Miyagi Cancer Center, Natori, Miyagi, Japan
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Ikoma T, Shimokawa M, Matsumoto T, Boku S, Yasuda T, Shibata N, Kurioka Y, Takatani M, Nobuhisa T, Namikawa T, Kitagawa H, Hanazaki K, Doi K, Shimada T, Tsumura T, Marusawa H, Kanaya S, Morita S, Inokuma T, Nagai H, Yasui H, Satake H. Inflammatory prognostic factors in advanced or recurrent esophageal squamous cell carcinoma treated with nivolumab. Cancer Immunol Immunother 2023; 72:427-435. [PMID: 35927359 PMCID: PMC10992512 DOI: 10.1007/s00262-022-03265-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 07/23/2022] [Indexed: 01/29/2023]
Abstract
BACKGROUND In Japan, nivolumab administration is the standard treatment for patients with unresectable advanced or recurrent esophageal squamous cell carcinoma (ESCC) who are refractory or intolerant to fluoropyrimidines and platinum-based chemotherapy. We determined if inflammatory prognostic factors are useful in patients with ESCC treated with nivolumab monotherapy. METHODS The clinical data of patients with ESCC treated with nivolumab monotherapy as the second- or later-line treatment were retrospectively analyzed. Neutrophil/lymphocyte, platelet/lymphocyte, and C-reactive protein/albumin ratios (CAR); prognostic index; and prognostic nutritional index were investigated. Cut-off values for each factor were determined according to overall survival using time-dependent receiver operating characteristic curves. RESULTS During January 2017-June 2021, 93 consecutive patients with ESCC were enrolled from five institutions (median age, 70 years; male, 77%). With a median follow-up period of 9.1 (range, 1.0-34.7) months, the median overall and progression-free survival were 12.8 (95% confidence interval [CI], 9.0-16.6) and 4.0 (95% CI, 2.6-5.4) months, respectively. Of five inflammatory prognostic factors, the cut-off value for CAR was 0.62; prognosis was significantly longer in those with CAR < 0.62 (hazard ratio, 0.39; 95% CI, 0.22-0.67; p = 0.001). CONCLUSIONS Inflammatory prognostic factors were useful in predicting prognosis for ESCC patients pretreated with nivolumab, especially for those with CAR < 0.62, suggesting that CAR adequately reflects prognosis.
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Affiliation(s)
- Tatsuki Ikoma
- Department of Medical Oncology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima minamimachi Chuo-ku, Kobe-shi, Hyogo-ken, 650-0047, Japan
- Cancer Treatment Center, Kansai Medical University Hospital, 2-3-1, Shinmachi, Hirakata-shi, Osaka-fu, 573-1191, Japan
| | - Mototsugu Shimokawa
- Department of Biostatistics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi,, Ube-shi, Yamaguchi-ken, 755-8505, Japan
| | - Toshihiko Matsumoto
- Department of Medical Oncology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima minamimachi Chuo-ku, Kobe-shi, Hyogo-ken, 650-0047, Japan
- Cancer Treatment Center, Kansai Medical University Hospital, 2-3-1, Shinmachi, Hirakata-shi, Osaka-fu, 573-1191, Japan
| | - Shogen Boku
- Cancer Treatment Center, Kansai Medical University Hospital, 2-3-1, Shinmachi, Hirakata-shi, Osaka-fu, 573-1191, Japan
| | - Tomoyo Yasuda
- Cancer Treatment Center, Kansai Medical University Hospital, 2-3-1, Shinmachi, Hirakata-shi, Osaka-fu, 573-1191, Japan
| | - Nobuhiro Shibata
- Cancer Treatment Center, Kansai Medical University Hospital, 2-3-1, Shinmachi, Hirakata-shi, Osaka-fu, 573-1191, Japan
| | - Yusuke Kurioka
- Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital, 1-12-1 Shimoteno, Himeji-shi, Hyogo-ken, 670-8540, Japan
| | - Masahiro Takatani
- Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital, 1-12-1 Shimoteno, Himeji-shi, Hyogo-ken, 670-8540, Japan
| | - Tetsuji Nobuhisa
- Department of Surgery, Japanese Red Cross Society Himeji Hospital, 1-12-1 Shimoteno,, Himeji-shi, Hyogo-ken, 670-8540, Japan
| | - Tsutomu Namikawa
- Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku-city, Kochi-ken, 783-8505, Japan
| | - Hiroyuki Kitagawa
- Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku-city, Kochi-ken, 783-8505, Japan
| | - Kazuhiro Hanazaki
- Department of Surgery, Kochi Medical School, Kohasu, Oko-cho, Nankoku-city, Kochi-ken, 783-8505, Japan
| | - Keitaro Doi
- Department of Medical Oncology, Japanese Red Cross Society Osaka Hospital, 5-30 Hudegasaki-cho, Tenouji-ku, Osaka-fu, 543-8555, Japan
| | - Takanobu Shimada
- Department of Medical Oncology, Japanese Red Cross Society Osaka Hospital, 5-30 Hudegasaki-cho, Tenouji-ku, Osaka-fu, 543-8555, Japan
| | - Takehiko Tsumura
- Department of Medical Oncology, Japanese Red Cross Society Osaka Hospital, 5-30 Hudegasaki-cho, Tenouji-ku, Osaka-fu, 543-8555, Japan
- Department of Gastroenterology and Hepatology, Japanese Red Cross Society Osaka Hospital, 5-30 Hudegasaki-cho, Tenouji-ku, Osaka-fu, 543-8555, Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and Hepatology, Japanese Red Cross Society Osaka Hospital, 5-30 Hudegasaki-cho, Tenouji-ku, Osaka-fu, 543-8555, Japan
| | - Seichiro Kanaya
- Department of Surgery, Japanese Red Cross Society Osaka Hospital, 5-30 Hudegasaki-cho,, Tenouji-ku, Osaka-fu, 543-8555, Japan
| | - Shuko Morita
- Department of Gastroenterology and Hepatology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima minamimachi Chuo-ku, Kobe-shi, Hyogo-ken, 650-0047, Japan
| | - Tetsurou Inokuma
- Department of Gastroenterology and Hepatology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima minamimachi Chuo-ku, Kobe-shi, Hyogo-ken, 650-0047, Japan
| | - Hiroki Nagai
- Department of Medical Oncology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima minamimachi Chuo-ku, Kobe-shi, Hyogo-ken, 650-0047, Japan
| | - Hisateru Yasui
- Department of Medical Oncology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima minamimachi Chuo-ku, Kobe-shi, Hyogo-ken, 650-0047, Japan
| | - Hironaga Satake
- Department of Medical Oncology, Kochi Medical School, Kohasu, Oko-cho, Nankoku-city, Kochi-ken, 783-8505, Japan.
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Giannotta C, Autino F, Massaia M. The immune suppressive tumor microenvironment in multiple myeloma: The contribution of myeloid-derived suppressor cells. Front Immunol 2023; 13:1102471. [PMID: 36726975 PMCID: PMC9885853 DOI: 10.3389/fimmu.2022.1102471] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 12/27/2022] [Indexed: 01/18/2023] Open
Abstract
Myeloid derived suppressors cells (MDSC) play major roles in regulating immune homeostasis and immune responses in many conditions, including cancer. MDSC interact with cancer cells within the tumor microenvironment (TME) with direct and indirect mechanisms: production of soluble factors and cytokines, expression of surface inhibitory molecules, metabolic rewiring and exosome release. The two-way relationship between MDSC and tumor cells results in immune evasion and cancer outgrowth. In multiple myeloma (MM), MDSC play a major role in creating protumoral TME conditions. In this minireview, we will discuss the interplay between MDSC and MM TME and the possible strategies to target MDSC.
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Affiliation(s)
- Claudia Giannotta
- Laboratorio di Immunologia dei Tumori del Sangue (LITS), Centro Interdipartimentale di Biotecnologie Molecolari “Guido Tarone”, Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Torino, Italy
| | - Federica Autino
- Laboratorio di Immunologia dei Tumori del Sangue (LITS), Centro Interdipartimentale di Biotecnologie Molecolari “Guido Tarone”, Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Torino, Italy
| | - Massimo Massaia
- Laboratorio di Immunologia dei Tumori del Sangue (LITS), Centro Interdipartimentale di Biotecnologie Molecolari “Guido Tarone”, Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Torino, Italy,SC Ematologia, AO S.Croce e Carle, Cuneo, Italy,*Correspondence: Massimo Massaia,
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Thangavel H, Lizardo K, Dhanyalayam D, De Assis S, Nagajyothi JF. Diets Differently Regulate Tumorigenesis in Young E0771 Syngeneic Breast Cancer Mouse Model. J Clin Med 2023; 12:413. [PMID: 36675341 PMCID: PMC9862441 DOI: 10.3390/jcm12020413] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/25/2022] [Accepted: 01/02/2023] [Indexed: 01/06/2023] Open
Abstract
Breast cancer (BC) is the most diagnosed cancer type, accounting for one in eight cancer diagnoses worldwide. Epidemiological studies have shown that obesity is associated with increased risk of BC in post-menopausal women, whereas adiposity reduces the risk of BC in premenopausal women. The mechanistic link between obesity and BC has been examined by combining murine BC models with high-fat diet (HFD) induced obesity. However, the effect of adiposity (not obesity) induced by a short period of HFD consumption on BC pathogenesis is not well understood. In the current study, we examined the effects of different diet compositions on BC pathogenesis using a young E0771 syngeneic BC mouse model fed on either an HFD or regular diet (RD: a low-fat high-carbohydrate diet) for a short period (4 weeks) before implanting mammary tumors in mice. We analyzed the effect of diet composition on the onset of tumor growth, metastasis, and metabolic and immune status in the tumor microenvironment (TME) using various methods including in vivo bioluminescence imaging and immunoblotting analyses. We showed for the first time that a short-term HFD delays the onset of tumorigenesis by altering the immune and metabolic signaling and energy mechanism in the TME. However, RD may increase the risk of tumorigenesis and metastasis by increasing pro-inflammatory factors in the TME in young mice. Our data suggest that diet composition, adipogenesis, and loss of body fat likely regulate the pathogenesis of BC in a manner that differs between young and post-menopausal subjects.
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Affiliation(s)
- Hariprasad Thangavel
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
| | - Kezia Lizardo
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
| | - Dhanya Dhanyalayam
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
| | - Sonia De Assis
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Jyothi F. Nagajyothi
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA
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Shah L, Latif A, Williams KJ, Mancuso E, Tirella A. Invasion and Secondary Site Colonization as a Function of In Vitro Primary Tumor Matrix Stiffness: Breast to Bone Metastasis. Adv Healthc Mater 2023; 12:e2201898. [PMID: 36351739 PMCID: PMC11468571 DOI: 10.1002/adhm.202201898] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/08/2022] [Indexed: 11/11/2022]
Abstract
Increased breast tissue stiffness is correlated with breast cancer risk and invasive cancer progression. However, its role in promoting bone metastasis, a major cause of mortality, is not yet understood. It is previously identified that the composition and stiffness of alginate-based hydrogels mimicking normal (1-2 kPa) and cancerous (6-10 kPa) breast tissue govern phenotype of breast cancer cells (including MDA-MB-231) in vitro. Here, to understand the causal effect of primary tumor stiffness on metastatic potential, a new breast-to-bone in vitro model is described. Together with alginate-gelatin hydrogels to mimic breast tissue, 3D printed biohybrid poly-caprolactone (PCL)-composite scaffolds, decellularized following bone-ECM deposition through Saos-2 engraftment, are used to mimic the bone tissue. It is reported that higher hydrogel stiffness results in the increased migration and invasion capacity of MDA-MB 231 cells. Interestingly, increased expression of osteolytic factors PTHrP and IL-6 is observed when MDA-MB-231 cells pre-conditioned in stiffer hydrogels (10 kPa, 3% w/v gelatin) colonize the bone/PCL scaffolds. The new breast-to-bone in vitro models herein described are designed with relevant tissue microenvironmental factors and could emerge as future non-animal technological platforms for monitoring metastatic processes and therapeutic efficacy.
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Affiliation(s)
- Lekha Shah
- Division of Pharmacy and OptometryFaculty of BiologyMedicine and HealthUniversity of ManchesterOxford RoadManchesterM13 9PLUK
- Present address:
BIOtech Center for Biomedical TechnologiesDepartment of Industrial EngineeringUniversity of TrentoVia delle Regole 101Trento38123Italy
| | - Ayşe Latif
- Division of Pharmacy and OptometryFaculty of BiologyMedicine and HealthUniversity of ManchesterOxford RoadManchesterM13 9PLUK
| | - Kaye J. Williams
- Division of Pharmacy and OptometryFaculty of BiologyMedicine and HealthUniversity of ManchesterOxford RoadManchesterM13 9PLUK
| | - Elena Mancuso
- Nanotechnology and Integrated Bio‐Engineering Centre (NIBEC)Ulster UniversityShore RoadNewtownabbeyBT37 0QBUK
- Present address:
Engineering Ingegneria Informatica S.P.A. ‐ R&D DivisionPiazzale dell'Agricoltura 24Rome00144Italy
| | - Annalisa Tirella
- Division of Pharmacy and OptometryFaculty of BiologyMedicine and HealthUniversity of ManchesterOxford RoadManchesterM13 9PLUK
- BIOtech – Center for Biomedical TechnologiesDepartment of Industrial EngineeringUniversity of TrentoVia delle Regole 101Trento38123Italy
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Li BH, Yan SY, Luo LS, Zeng XT, Wang YB, Wang XH. Ten interleukins and risk of prostate cancer. Front Oncol 2023; 13:1108633. [PMID: 36733309 PMCID: PMC9887118 DOI: 10.3389/fonc.2023.1108633] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 01/02/2023] [Indexed: 01/18/2023] Open
Abstract
Background Interleukins (ILs) have been reported to be related to prostate cancer. The aims of this study were to estimate the levels for several key interleukins in prostate cancer and the causal effects between them. Methods We conducted a bi-directional two-sample Mendelian randomization (MR) study to assess the causal associations between ILs and prostate cancer. Genetic instruments and summary-level data for 10 ILs were obtained from three genome-wide association meta-analyses. Prostate cancer related data were obtained from the PRACTICAL (79,148 cases and 61,106 controls), UK Biobank (7,691 cases and 169,762 controls) and FinnGen consortium (10,414 cases and 124,994 controls), respectively. Results The odds ratio of prostate cancer was 0.92 (95% confidence interval (CI), 0.89, 0.96; P=1.58×10-05) and 1.12 (95% CI, 1.07, 1.17; P=6.61×10-07) for one standard deviation increase in genetically predicted IL-1ra and IL-6 levels, respectively. Genetically predicted levels of IL-1ß, IL-2a, IL-6ra, IL-8, IL-16, IL-17, IL-18, and IL-27 were not associated with the risk of prostate cancer. Reverse MR analysis did not find the associations between genetic liability to prostate cancer and higher levels of IL-1ra (β, -0.005; 95% CI, -0.010, 0.001; P=0.111) and IL-6 (β, 0.002; 95% CI, -0.011, 0.014; P=0.755). Conclusion This MR study suggests that long-term IL-6 may increase the risk of prostate cancer and IL-1ra may reduce it.
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Affiliation(s)
- Bing-Hui Li
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Si-Yu Yan
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Li-Sha Luo
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xian-Tao Zeng
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yong-Bo Wang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
- *Correspondence: Xing-Huan Wang, ; Yong-Bo Wang,
| | - Xing-Huan Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
- *Correspondence: Xing-Huan Wang, ; Yong-Bo Wang,
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Chen L, Zhang S, Li Q, Li J, Deng H, Zhang S, Meng R. Emerging role of Protein Kinase CK2 in Tumor immunity. Front Oncol 2022; 12:1065027. [DOI: 10.3389/fonc.2022.1065027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 11/11/2022] [Indexed: 12/03/2022] Open
Abstract
Protein kinase CK2, a conserved serine/threonine-protein kinase, is ubiquitous in cells and regulates various intracellular processes, especially in tumor cells. As one of the earliest discovered protein kinases in humans, CK2 plays a crucial role in phosphorylating or associating with hundreds of substrates to modulate several signaling pathways. Excellent reviews have reported that the overexpression of CK2 could be observed in many cancers and was closely associated with tumor occurrence and development. The elevation of CK2 is also an indicator of a poor prognosis. Recently, increasing attention has been paid to the relationship between CK2 and tumor immunity. However, there is no comprehensive description of how CK2 regulates the immune cells in the tumor microenvironment (TME). Also, the underlying mechanisms are still not very clear. In this review, we systematically summarized the correlation between CK2 and tumor immunity, primarily the effects on various immune cells, both in innate and adaptive immunity in the TME. With the comprehensive development of immunotherapy and the mounting transformation research of CK2 inhibitors from the bench to the clinic, this review will provide vital information to find new treatment options for enhancing the efficacy of immunotherapy.
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Tong Y, Cao Y, Jin T, Huang Z, He Q, Mao M. Role of Interleukin-1 family in bone metastasis of prostate cancer. Front Oncol 2022; 12:951167. [PMID: 36237303 PMCID: PMC9552844 DOI: 10.3389/fonc.2022.951167] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 09/12/2022] [Indexed: 11/28/2022] Open
Abstract
Prostate cancer (PCa) is one of the most fatal diseases in male patients with high bone metastatic potential. Bone metastasis severely shortens overall survival and brings skeletal-related events (SREs) which reduces the life quality of patients, and this situation is currently regarded as irreversible and incurable. The progression and metastasis of PCa are found to be closely associated with inflammatory cytokines and chemokines. As pivotal members of inflammatory cytokines, Interleukin-1 (IL-1) family plays a crucial role in this process. Elevated expression of IL-1 family was detected in PCa patients with bone metastasis, and accumulating evidences proved that IL-1 family could exert vital effects on the progression and bone metastasis of many cancers, while some members have dual effects. In this review, we discuss the role of IL-1 family in the bone metastasis of PCa. Furthermore, we demonstrate that many members of IL-1 family could act as pivotal biomarkers to predict the clinical stage and prognosis of PCa patients. More importantly, we have elucidated the role of IL-1 family in the bone metastasis of PCa, which could provide potential targets for the treatment of PCa bone metastasis and probable directions for future research.
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Affiliation(s)
- Yuanhao Tong
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Yinghao Cao
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tianzhe Jin
- Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhengwei Huang
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Qinyuan He
- Organization Department, Suzhou Traditional Chinese Medicine Hospital, Suzhou, China
| | - Min Mao
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Min Mao,
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Elmas O, Sahin HHK, Guven B, Abuzaid MM, Elshami W, ALMisned G, Zakaly HMH, Ene A, Tekin HO. A focusing study on radioprotective and antioxidant effects of Annona muricata leaf extract in the circulation and liver tissue: Clinical and experimental studies. OPEN CHEM 2022. [DOI: 10.1515/chem-2022-0206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Abstract
Objectives
This study investigates the effect of Annona muricata (AM) leaf extract against irradiation-induced damage by the evaluation of hepatic tissue and the levels of oxidative and inflammatory stress in the circulation.
Methods
An experimental study with 37 female Wistar albino rats randomized into four groups (controls and three intervention groups) was performed. The first interventional group (group 2) received 300 mg/kg of AM leaf extract by oral gavage once a day for 9 days, group 3 received a single dose of whole-body radiation (8.3 Gy) after a 9-day oral gavage treatment with saline, and the last group received the same irradiation of 8.3 Gy after being treated with 300 mg/kg of AM leaf extract by oral gavage once a day for 9 days.
Results
Radiation was found to elevate reactive oxygen species parameters, and AM administration before irradiation was found to decrease total oxidant status (TOS), increase caspase 9, and improve hepatic damage when compared with the group that received only irradiation.
Conclusion
The damage caused by irradiation may be ameliorated by the use of the AM extract, which appears to be effective in preventing oxidative stress and inflammatory activity.
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Affiliation(s)
- Ozlem Elmas
- Department of Radiation Oncology, Bulent Ecevit University Practice and Research Hospital , Zonguldak , Turkey
| | - Havva Hande Keser Sahin
- Department of Pathology, Hitit University Corum Training and Research Hospital , Corum , Turkey
| | - Berrak Guven
- Department of Biochemistry, Bulent Ecevit University Practice and Research Hospital , Zonguldak , Turkey
| | - Mohamed M. Abuzaid
- Department of Medical Diagnostic Imaging, College of Health Sciences, University of Sharjah , Sharjah , United Arab Emirates
| | - Wiam Elshami
- Department of Medical Diagnostic Imaging, College of Health Sciences, University of Sharjah , Sharjah , United Arab Emirates
| | - Ghada ALMisned
- Department of Physics, College of Science, Princess Nourah Bint Abdulrahman University , P.O. Box 84428 , Riyadh 11671 , Saudi Arabia
| | - Hesham M. H. Zakaly
- Institute of Physics and Technology, Ural Federal University , 620002 Ekaterinburg , Russia
- Physics Department, Faculty of Science, Al-Azhar University , Assiut 71524 , Egypt
| | - Antoaneta Ene
- Department of Chemistry, Physics and Environment, Faculty of Sciences and Environment, INPOLDE Research Center, Dunarea de Jos University of Galati , 47 Domneasca Street , 800008 Galati , Romania
| | - Huseyin Ozan Tekin
- Department of Medical Diagnostic Imaging, College of Health Sciences, University of Sharjah , Sharjah , United Arab Emirates
- Computer Engineering Department, Faculty of Engineering and Natural Sciences, Istinye University , Istanbul , 34396 , Turkey
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40
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Chen J, Wei Y, Yang W, Huang Q, Chen Y, Zeng K, Chen J. IL-6: The Link Between Inflammation, Immunity and Breast Cancer. Front Oncol 2022; 12:903800. [PMID: 35924148 PMCID: PMC9341216 DOI: 10.3389/fonc.2022.903800] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 06/20/2022] [Indexed: 11/24/2022] Open
Abstract
Breast cancer is one of the leading causes of mortality in females. Over the past decades, intensive efforts have been made to uncover the pathogenesis of breast cancer. Interleukin-6 (IL-6) is a pleiotropic factor which has a vital role in host defense immunity and acute stress. Moreover, a wide range of studies have identified the physiological and pathological roles of IL-6 in inflammation, immune and cancer. Recently, several IL-6 signaling pathway-targeted monoclonal antibodies have been developed for cancer and immune therapy. Combination of IL-6 inhibitory antibody with other pathways blockage drugs have demonstrated promising outcome in both preclinical and clinical trials. This review focuses on emerging studies on the strong linkages of IL-6/IL-6R mediated regulation of inflammation and immunity in cancer, especially in breast cancer.
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Affiliation(s)
- Juan Chen
- Department of Medicine and Rehabilitation, Tung Wah Eastern Hospital, Hong Kong, Hong Kong SAR, China
| | - Yanghui Wei
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
- *Correspondence: Yanghui Wei, ; Jiawei Chen,
| | - Weiqin Yang
- School of Biomedical Sciences, The Chinese, University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Qingnan Huang
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Yong Chen
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Kai Zeng
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Jiawei Chen
- Department of Surgery, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
- *Correspondence: Yanghui Wei, ; Jiawei Chen,
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Liu D, Luo X, Xie M, Zhang T, Chen X, Zhang B, Sun M, Wang Y, Feng Y, Ji X, Li Y, Liu B, Huang W, Xia L. HNRNPC downregulation inhibits IL-6/STAT3-mediated HCC metastasis by decreasing HIF1A expression. Cancer Sci 2022; 113:3347-3361. [PMID: 35848884 PMCID: PMC9530878 DOI: 10.1111/cas.15494] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 06/13/2022] [Accepted: 07/01/2022] [Indexed: 11/29/2022] Open
Abstract
RNA‐binding protein (RBP) dysregulation is functionally linked to several human diseases, including neurological disorders, cardiovascular disease, and cancer. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a diverse family of RBPs involved in nucleic acid metabolism. A growing body of studies has shown that the dysregulated hnRNPs play important roles in tumorigenesis. Here, we found that heterogeneous nuclear ribonucleoprotein C (C1/C2) (HNRNPC) had good performance in distinguishing between hepatocellular carcinoma (HCC) and normal liver tissues through bioinformatics analysis. Further investigation revealed that HNRNPC was significantly correlated with multiple malignant characteristics of HCC, including tumor size, microvascular invasion, tumor differentiation, and TNM stage. Patients with HCC with positive HNRNPC expression exhibited decreased overall survival and increased recurrence rate. HNRNPC downregulation inhibited HCC invasion and metastasis. The decreased expression of hypoxia inducible factor 1 subunit alpha (HIF1A) was identified as the molecular mechanism underlying HNRNPC downregulation‐inhibited HCC metastasis by RNA sequencing. Mechanistically, HNRNPC downregulation decreased HIF1A expression by destabilizing HIF1A mRNA. HIF1A overexpression rescued the decrease in invasiveness and metastasis of HCC induced by HNRNPC downregulation. Additionally, interleukin (IL)‐6/STAT3 signaling upregulated HNRNPC expression in HCC cells, and knockdown of HNRNPC significantly inhibited IL‐6/STAT3‐enhanced HCC metastasis. Furthermore, anti‐IL‐6 antibody siltuximab significantly inhibited IL‐6‐mediated HCC metastasis. In summary, our research revealed the clinical value, functional role, and molecular mechanism of HNRNPC in HCC and showed the potential of HNRNPC as a biomarker for diagnosis, prognosis, and further therapeutic targets for HCC.
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Affiliation(s)
- Danfei Liu
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiangyuan Luo
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Meng Xie
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Tongyue Zhang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiaoping Chen
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases; Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Clinical Medicine Research Center for Hepatic Surgery of Hubei Province; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei, China
| | - Bixiang Zhang
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases; Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Clinical Medicine Research Center for Hepatic Surgery of Hubei Province; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei, China
| | - Mengyu Sun
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yijun Wang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yangyang Feng
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiaoyu Ji
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yiwei Li
- The Key Laboratory for Biomedical Photonics of MOE at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics and Molecular Imaging Key Laboratory, Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Bifeng Liu
- The Key Laboratory for Biomedical Photonics of MOE at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics and Molecular Imaging Key Laboratory, Systems Biology Theme, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjie Huang
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases; Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Clinical Medicine Research Center for Hepatic Surgery of Hubei Province; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei, China
| | - Limin Xia
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Kajihara R, Sakai H, Han Y, Amari K, Kawamoto M, Hakoyama Y, Nagashio S, Yamada SI, Sanjo H, Kurita H. Presence of periodontitis may synergistically contribute to cancer progression via Treg and IL-6. Sci Rep 2022; 12:11584. [PMID: 35804048 PMCID: PMC9270385 DOI: 10.1038/s41598-022-15690-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 06/28/2022] [Indexed: 11/09/2022] Open
Abstract
A close causal relationship has been suggested to exist between cancer and periodontitis. We hypothesized that the immune surveillance system is impaired in patients with periodontitis, which contributes to cancer development and growth. Therefore, the present study investigated the relationship between immune surveillance mechanisms and periodontitis in cancer patients. The presence or absence of periodontitis was assessed and the peripheral blood (PB) concentrations of IL-6, immunosuppressive cytokines (VEGF, TGF-β1, and CCL22) and proportion of T regulatory cells (Treg, CD3 + CD4 + CD25 + Foxp3 +) were measured. Subjects were classified into the following four groups: non-cancer patients without periodontitis (C − P −), non-cancer patients with periodontitis (C − P +), cancer patients without periodontitis (C + P −), and cancer patients with periodontitis (C + P +). The results of a multivariate analysis showed that the PB concentration of IL-6 was significantly higher in C + than in C- and higher in C + P + than in C + P −. The PB proportion of Treg was significantly higher in C + P + than in C + P −, C − P + , and C − P −. The results of this study suggested that the presence of periodontitis and cancer synergistically increased Treg in PB, which may be one of the underlying causes of immunosuppression and immune evasion in cancer. It was also suggested that the presence of periodontal disease and/or cancer also increases IL-6 in PB, which would be associated with cancer progression. These results suggest the possibility that the presence of periodontitis might synergistically contribute to cancer progression.
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Affiliation(s)
- Ryo Kajihara
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Hironori Sakai
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan.
| | - Yibing Han
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Kei Amari
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Makiko Kawamoto
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Yusuke Hakoyama
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Sachiho Nagashio
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Shin-Ichi Yamada
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Hideki Sanjo
- Department of Molecular and Cellular Immunology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hiroshi Kurita
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
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43
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Qian S, Ding M, Hou H, Wang Z, Zhang J, Zhang Y, Dong M, Zhu L, Wang G, Li W, Zhang X. Clinical and Molecular Characteristics of 60 Patients With Human Immunodeficiency Virus-Negative Castleman Disease. Front Immunol 2022; 13:899073. [PMID: 35655778 PMCID: PMC9152317 DOI: 10.3389/fimmu.2022.899073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 04/19/2022] [Indexed: 11/29/2022] Open
Abstract
Castleman disease (CD) is a rare lymphoproliferative disorder. The mechanistic target of rapamycin (mTOR) pathway is a key regulator of various cellular functions, which may be related with the potential mechanisms of CD occurrence. We retrospectively collected the clinical information of 60 CD patients diagnosed in the First Affiliated Hospital of Zhengzhou University. And FFPE biopsy specimens were collected from 31 patients (12 unicentric CD patients and 19 multicentric CD patients) to detect the mTOR pathway protein expression. We are the first to demonstrate that thrombocytopenia and hypoalbuminemia are independent poor prognostic factors for CD. Moreover, mTOR activation was higher in CD compared to reactive lymphoid hyperplasia (used as a control group). This study offers some elucidation for the management and treatment of CD patients.
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Affiliation(s)
- Siyu Qian
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Mengjie Ding
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Huting Hou
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Zeyuan Wang
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Jieming Zhang
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Yue Zhang
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Meng Dong
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Linan Zhu
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Guannan Wang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wencai Li
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xudong Zhang
- Department of Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
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44
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Sakowska J, Arcimowicz Ł, Jankowiak M, Papak I, Markiewicz A, Dziubek K, Kurkowiak M, Kote S, Kaźmierczak-Siedlecka K, Połom K, Marek-Trzonkowska N, Trzonkowski P. Autoimmunity and Cancer-Two Sides of the Same Coin. Front Immunol 2022; 13:793234. [PMID: 35634292 PMCID: PMC9140757 DOI: 10.3389/fimmu.2022.793234] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 04/12/2022] [Indexed: 02/06/2023] Open
Abstract
Autoimmune disease results from the immune response against self-antigens, while cancer develops when the immune system does not respond to malignant cells. Thus, for years, autoimmunity and cancer have been considered as two separate fields of research that do not have a lot in common. However, the discovery of immune checkpoints and the development of anti-cancer drugs targeting PD-1 (programmed cell death receptor 1) and CTLA-4 (cytotoxic T lymphocyte antigen 4) pathways proved that studying autoimmune diseases can be extremely helpful in the development of novel anti-cancer drugs. Therefore, autoimmunity and cancer seem to be just two sides of the same coin. In the current review, we broadly discuss how various regulatory cell populations, effector molecules, genetic predisposition, and environmental factors contribute to the loss of self-tolerance in autoimmunity or tolerance induction to cancer. With the current paper, we also aim to convince the readers that the pathways involved in cancer and autoimmune disease development consist of similar molecular players working in opposite directions. Therefore, a deep understanding of the two sides of immune tolerance is crucial for the proper designing of novel and selective immunotherapies.
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Affiliation(s)
- Justyna Sakowska
- Department of Medical Immunology, Medical University of Gdańsk, Gdańsk, Poland
| | - Łukasz Arcimowicz
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | - Martyna Jankowiak
- Department of Medical Immunology, Medical University of Gdańsk, Gdańsk, Poland
| | - Ines Papak
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | - Aleksandra Markiewicz
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland
| | - Katarzyna Dziubek
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | - Małgorzata Kurkowiak
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | - Sachin Kote
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | | | - Karol Połom
- Department of Surgical Oncology, Medical University of Gdańsk, Gdańsk, Poland
| | - Natalia Marek-Trzonkowska
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
- Laboratory of Immunoregulation and Cellular Therapies, Department of Family Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Piotr Trzonkowski
- Department of Medical Immunology, Medical University of Gdańsk, Gdańsk, Poland
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45
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Lawther AJ, Phillips AJK, Chung NC, Chang A, Ziegler AI, Debs S, Sloan EK, Walker AK. Disrupting circadian rhythms promotes cancer-induced inflammation in mice. Brain Behav Immun Health 2022; 21:100428. [PMID: 35199050 PMCID: PMC8851215 DOI: 10.1016/j.bbih.2022.100428] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 02/07/2022] [Accepted: 02/07/2022] [Indexed: 02/09/2023] Open
Abstract
Disruption of circadian rhythms occurs in rotating shift-work, jetlag, and in individuals with irregular sleep schedules. Circadian disruption is known to alter inflammatory responses and impair immune function. However, there is limited understanding of how circadian disruption modulates cancer-induced inflammation. Inflammation is a hallmark of cancer and is linked to worse prognosis and impaired brain function in cancer patients. Here, we investigated the effect of circadian disruption on cancer-induced inflammation in an orthotopic breast cancer model. Using a validated chronic jetlag protocol that advances the light-cycle by 8 h every 2 days to disrupt circadian rhythms, we found that circadian disruption alters cancer-induced inflammation in a tissue-specific manner, increasing inflammation in the body and brain while decreasing inflammation within the tumor tissue. Circadian disruption did not affect inflammation in mice without tumors, suggesting that the impact of circadian disruption may be particularly detrimental in the context of underlying inflammatory conditions, such as cancer. Importantly, circadian disruption did not affect tumor burden, suggesting that increased inflammation was not a result of increased cancer progression. Overall, these findings identify the importance of healthy circadian rhythms for limiting cancer-induced inflammation.
Circadian disruption enhances cancer-induced inflammation in the body and brain. The profile of inflammatory cytokines altered by circadian disruption is tissue specific. Changes in inflammatory profiles by circadian disruption are not due to enhanced tumor burden.
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Affiliation(s)
- Adam J Lawther
- Laboratory of ImmunoPsychiatry, Neuroscience Research Australia, Randwick, New South Wales, 2031, Australia
| | - Andrew J K Phillips
- Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Clayton, VIC, 3800, Australia
| | - Ni-Chun Chung
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia
| | - Aeson Chang
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia
| | - Alexandra I Ziegler
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia
| | - Sophie Debs
- Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, New South Wales, 2031, Australia
| | - Erica K Sloan
- Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.,Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, VIC, 3002, Australia
| | - Adam K Walker
- Laboratory of ImmunoPsychiatry, Neuroscience Research Australia, Randwick, New South Wales, 2031, Australia.,Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.,School of Psychiatry, University of New South Wales, Kensington, NSW, 2033, Australia
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46
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Manore SG, Doheny DL, Wong GL, Lo HW. IL-6/JAK/STAT3 Signaling in Breast Cancer Metastasis: Biology and Treatment. Front Oncol 2022; 12:866014. [PMID: 35371975 PMCID: PMC8964978 DOI: 10.3389/fonc.2022.866014] [Citation(s) in RCA: 140] [Impact Index Per Article: 46.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 02/16/2022] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most commonly diagnosed cancer in women. Metastasis is the primary cause of mortality for breast cancer patients. Multiple mechanisms underlie breast cancer metastatic dissemination, including the interleukin-6 (IL-6)-mediated signaling pathway. IL-6 is a pleiotropic cytokine that plays an important role in multiple physiological processes including cell proliferation, immune surveillance, acute inflammation, metabolism, and bone remodeling. IL-6 binds to the IL-6 receptor (IL-6Rα) which subsequently binds to the glycoprotein 130 (gp130) receptor creating a signal transducing hexameric receptor complex. Janus kinases (JAKs) are recruited and activated; activated JAKs, in turn, phosphorylate signal transducer and activator of transcription 3 (STAT3) for activation, leading to gene regulation. Constitutively active IL-6/JAK/STAT3 signaling drives cancer cell proliferation and invasiveness while suppressing apoptosis, and STAT3 enhances IL-6 signaling to promote a vicious inflammatory loop. Aberrant expression of IL-6 occurs in multiple cancer types and is associated with poor clinical prognosis and metastasis. In breast cancer, the IL-6 pathway is frequently activated, which can promote breast cancer metastasis while simultaneously suppressing the anti-tumor immune response. Given these important roles in human cancers, multiple components of the IL-6 pathway are promising targets for cancer therapeutics and are currently being evaluated preclinically and clinically for breast cancer. This review covers the current biological understanding of the IL-6 signaling pathway and its impact on breast cancer metastasis, as well as, therapeutic interventions that target components of the IL-6 pathway including: IL-6, IL-6Rα, gp130 receptor, JAKs, and STAT3.
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Affiliation(s)
- Sara G Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Daniel L Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Grace L Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, United States.,Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, United States
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47
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Tu CF, Li FA, Li LH, Yang RB. Quantitative glycoproteomics analysis identifies novel FUT8 targets and signaling networks critical for breast cancer cell invasiveness. Breast Cancer Res 2022; 24:21. [PMID: 35303925 PMCID: PMC8932202 DOI: 10.1186/s13058-022-01513-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 02/25/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND We recently showed that fucosyltransferase 8 (FUT8)-mediated core fucosylation of transforming growth factor-β receptor enhances its signaling and promotes breast cancer invasion and metastasis. However, the complete FUT8 target glycoproteins and their downstream signaling networks critical for breast cancer progression remain largely unknown. METHOD We performed quantitative glycoproteomics with two highly invasive breast cancer cell lines to unravel a comprehensive list of core-fucosylated glycoproteins by comparison to parental wild-type and FUT8-knockout counterpart cells. In addition, ingenuity pathway analysis (IPA) was performed to highlight the most enriched biological functions and signaling pathways mediated by FUT8 targets. Novel FUT8 target glycoproteins with biological interest were functionally studied and validated by using LCA (Lens culinaris agglutinin) blotting and LC-MS/MS (liquid chromatography-tandem mass spectrometry) analysis. RESULTS Loss-of-function studies demonstrated that FUT8 knockout suppressed the invasiveness of highly aggressive breast carcinoma cells. Quantitative glycoproteomics identified 140 common target glycoproteins. Ingenuity pathway analysis (IPA) of these target proteins gave a global and novel perspective on signaling networks essential for breast cancer cell migration and invasion. In addition, we showed that core fucosylation of integrin αvβ5 or IL6ST might be crucial for breast cancer cell adhesion to vitronectin or enhanced cellular signaling to interleukin 6 and oncostatin M, two cytokines implicated in the breast cancer epithelial-mesenchymal transition and metastasis. CONCLUSIONS Our report reveals a comprehensive list of core-fucosylated target proteins and provides novel insights into signaling networks crucial for breast cancer progression. These findings will assist in deciphering the complex molecular mechanisms and developing diagnostic or therapeutic approaches targeting these signaling pathways in breast cancer metastasis.
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Affiliation(s)
- Cheng-Fen Tu
- Institute of Biomedical Sciences, Academia Sinica, 128 Academia Rd., Sec. 2, Taipei, 115201, Taiwan
| | - Fu-An Li
- Institute of Biomedical Sciences, Academia Sinica, 128 Academia Rd., Sec. 2, Taipei, 115201, Taiwan
| | - Ling-Hui Li
- Institute of Biomedical Sciences, Academia Sinica, 128 Academia Rd., Sec. 2, Taipei, 115201, Taiwan
| | - Ruey-Bing Yang
- Institute of Biomedical Sciences, Academia Sinica, 128 Academia Rd., Sec. 2, Taipei, 115201, Taiwan. .,Biomedical Translation Research Center, Academia Sinica, Taipei, 115202, Taiwan. .,Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, 110301, Taiwan.
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Bedhiafi T, Inchakalody VP, Fernandes Q, Mestiri S, Billa N, Uddin S, Merhi M, Dermime S. The potential role of vitamin C in empowering cancer immunotherapy. Biomed Pharmacother 2022; 146:112553. [PMID: 34923342 DOI: 10.1016/j.biopha.2021.112553] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 12/01/2021] [Accepted: 12/13/2021] [Indexed: 12/12/2022] Open
Abstract
Vitamin C also known as L-ascorbic acid is a nutrient naturally occurring in many fruits and vegetables and widely known for its potent antioxidant activity. Several studies have highlighted the importance of using high dose vitamin C as an adjuvant anti-cancer therapy. Interestingly, it has been shown that vitamin C is able to modulate the anti-cancer immune response and to help to overcome the resistance to immune checkpoints blockade (ICB) drugs such as cytotoxic T-lymphocyte antigen 4 (CLTA-4) and programmed cell death ligand 1 (PD-L1/PD-1) inhibitors. Indeed, it was reported that vitamin C regulates several mechanisms developed by cancer cells to escape T cells immune response and resist ICB. Understanding the role of vitamin C in the anti-tumor immune response will pave the way to the development of novel combination therapies that would enhance the response of cancer patients to ICB immunotherapy. In this review, we discuss the effect of vitamin C on the immune system and its potential role in empowering cancer immunotherapy through its pro-oxidant potential, its ability to modulate epigenetic factors and its capacity to regulate the expression of different cytokines involved in the immune response.
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Affiliation(s)
- Takwa Bedhiafi
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Varghese Philipose Inchakalody
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Queenie Fernandes
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; College of Medicine, Qatar University, Doha, Qatar
| | - Sarra Mestiri
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | | | - Shahab Uddin
- Translational Research Institute and dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha 2713, Qatar
| | - Maysaloun Merhi
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.
| | - Said Dermime
- Translational Cancer Research Facility, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar; National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
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Li M, Jin S, Zhang Z, Ma H, Yang X. Interleukin-6 facilitates tumor progression by inducing ferroptosis resistance in head and neck squamous cell carcinoma. Cancer Lett 2021; 527:28-40. [PMID: 34902522 DOI: 10.1016/j.canlet.2021.12.011] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/16/2021] [Accepted: 12/08/2021] [Indexed: 12/18/2022]
Abstract
Ferroptosis resistance is an important mechanism of tumor progression. Interleukin-6 (IL-6) is a representative inflammatory cytokine during chronic inflammation; however, our current understanding of its regulatory role of ferroptosis during carcinogenesis of head and neck squamous cell carcinoma is limited. Chromatin immunoprecipitation and functional observations were performed to investigate xCT-regulatory function of IL-6. We observed a gradual increase in lipid peroxide 4-hydroxynonenal and IL-6 levels during progression from normal oral mucosa to leukoplakia and HNSCC. Meanwhile, the expression of xCT, a key amino acid antiporter assisting ferroptosis resistance, was correlated with IL-6 levels. The upregulated expression of xCT in HNSCC is associated with poor prognosis. Silencing of xCT inhibited HNSCC cell proliferation in vitro and tumor growth in vivo, inducing ferroptosis. Mechanistically, IL-6 transcriptionally activates xCT expression through the JAK2/STAT3 pathway. Furthermore, IL-6 reversed ferroptosis and growth suppression that was induced by xCT knockdown or ferroptosis inducer erastin. Our results demonstrate the critical role of IL-6-induced ferroptosis resistance during HNSCC carcinogenesis. The IL-6/STAT3/xCT axis acts as a novel mechanism driving tumor progression and thus may potentially be utilized as a target for tumor prevention and therapy.
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Affiliation(s)
- Mingyu Li
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai, 200011, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, No. 639, Zhizaoju Rd, Shanghai, 200011, China; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, No. 639, Zhizaoju Rd, Shanghai, 200011, China.
| | - Shufang Jin
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai, 200011, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, No. 639, Zhizaoju Rd, Shanghai, 200011, China; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, No. 639, Zhizaoju Rd, Shanghai, 200011, China.
| | - Zhiyuan Zhang
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai, 200011, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, No. 639, Zhizaoju Rd, Shanghai, 200011, China; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, No. 639, Zhizaoju Rd, Shanghai, 200011, China.
| | - Hailong Ma
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai, 200011, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, No. 639, Zhizaoju Rd, Shanghai, 200011, China; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, No. 639, Zhizaoju Rd, Shanghai, 200011, China.
| | - Xi Yang
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai, 200011, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, No. 639, Zhizaoju Rd, Shanghai, 200011, China; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, No. 639, Zhizaoju Rd, Shanghai, 200011, China.
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Shi Y, Liu X, Du J, Zhang D, Liu J, Chen M, Zhao J, Zhong W, Xu Y, Wang M. Circulating cytokines associated with clinical outcomes in advanced non-small cell lung cancer patients who received chemoimmunotherapy. Thorac Cancer 2021; 13:219-227. [PMID: 34825500 PMCID: PMC8758427 DOI: 10.1111/1759-7714.14248] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 12/22/2022] Open
Abstract
Background Pretreatment and on‐treatment plasma cytokine levels in predicting clinical benefit in patients with advanced non‐small cell lung cancer (NSCLC) treated with anti‐programmed death‐1 (PD‐1)‐based chemotherapy is still a matter of debate. Methods We measured 12 kind of plasma cytokines in patients with stage III/IV NSCLC before and during treatment with anti‐PD‐1 based chemotherapy. Associations with best overall response, and survival including progression‐free survival (PFS) and overall survival (OS) were assessed using Chi‐square test and Kaplan–Meier plots with log‐rank test, respectively. Logistic regression and Cox regression were used to determine independent risk factors. Results Of a total of 60 patients, high‐level of pretreatment interleukin‐2 was associated with longer PFS (log rank p = 0.049), while high‐level of pretreatment interleukin‐8 was associated with shorter OS (log rank p = 0.006). Increased on‐treatment interleukin‐1β (IL‐1β) was associated with both better response (odds ratio [OR] 6.233, 95% confidential interval [CI]: 1.451–26.344, p = 0.013) and longer PFS (hazard ratio [HR] 0.305, 95% CI: 0.127–0.730, p = 0.008). On the contrary, increased on‐treatment interleukin‐6 (IL‐6) was associated with a worse response (OR 0.015, 95% CI: 0.001–0.400, p = 0.012), worse PFS (HR 2.639, 95% CI: 1.163–5.991, p = 0.020) and worse OS (HR 2.742, 95% CI: 1.063–7.074, p = 0.037). Increased interferon‐γ (IFN‐γ) was found to be associated with better PFS (HR 0.336, 95% CI: 0.153–0.745, p = 0.007). Conclusions In patients with advanced NSCLC who received chemoimmunotherapy, on‐treatment increased IL‐1β and IFN‐γ may serve as positive indicator of efficacy, while on‐treatment increased IL‐6 might play a predictive role of worse clinical outcome.
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Affiliation(s)
- Yuequan Shi
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaoyan Liu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Juan Du
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Dongming Zhang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jia Liu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Minjiang Chen
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jing Zhao
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Wei Zhong
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yan Xu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Mengzhao Wang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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