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Li W, Liu N, Chen M, Liu D, Liu S. Metformin as an immunomodulatory agent in enhancing head and neck squamous cell carcinoma therapies. Biochim Biophys Acta Rev Cancer 2025; 1880:189262. [PMID: 39827973 DOI: 10.1016/j.bbcan.2025.189262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 12/23/2024] [Accepted: 01/06/2025] [Indexed: 01/22/2025]
Abstract
Head and neck squamous cell carcinoma (HNSCC) remains a significant clinical challenge due to its aggressive behavior and poor prognosis, making the development of novel therapeutics with enhanced efficacy and minimal side effects critical. Metformin, a widely used antidiabetic agent, has recently emerged as a potential adjunctive therapy for HNSCC, exhibiting both direct anti-tumor and immunomodulatory effects. This review comprehensively explores the multifaceted role of metformin in shaping the tumor immune microenvironment within HNSCC. We emphasize its pivotal role in modulating immune cell populations and its potential for synergistic action with immunotherapeutic strategies. Furthermore, we address the current challenges associated with optimizing dosing regimens, identifying predictive biomarkers, and integrating metformin with immunotherapy. By dissecting these aspects, this review aims to pave the way for the development of personalized HNSCC treatment strategies that fully exploit the therapeutic potential of metformin.
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Affiliation(s)
- Wenting Li
- Department of Dental Materials, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No. 117 Nanjing North Street, Heping District, Shenyang 110002, Liaoning, China
| | - Nanshu Liu
- Department of Emergency and Oral Medicine, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No. 117 Nanjing North Street, Heping District, Shenyang 110002, Liaoning, China
| | - Mingwei Chen
- Department of Dental Materials, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No. 117 Nanjing North Street, Heping District, Shenyang 110002, Liaoning, China
| | - Dongjuan Liu
- Department of Emergency and Oral Medicine, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No. 117 Nanjing North Street, Heping District, Shenyang 110002, Liaoning, China.
| | - Sai Liu
- Department of Dental Materials, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, No. 117 Nanjing North Street, Heping District, Shenyang 110002, Liaoning, China.
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Jia H, Chen X, Zhang L, Chen M. Cancer associated fibroblasts in cancer development and therapy. J Hematol Oncol 2025; 18:36. [PMID: 40156055 PMCID: PMC11954198 DOI: 10.1186/s13045-025-01688-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 03/12/2025] [Indexed: 04/01/2025] Open
Abstract
Cancer-associated fibroblasts (CAFs) are key players in cancer development and therapy, and they exhibit multifaceted roles in the tumor microenvironment (TME). From their diverse cellular origins, CAFs undergo phenotypic and functional transformation upon interacting with tumor cells and their presence can adversely influence treatment outcomes and the severity of the cancer. Emerging evidence from single-cell RNA sequencing (scRNA-seq) studies have highlighted the heterogeneity and plasticity of CAFs, with subtypes identifiable through distinct gene expression profiles and functional properties. CAFs influence cancer development through multiple mechanisms, including regulation of extracellular matrix (ECM) remodeling, direct promotion of tumor growth through provision of metabolic support, promoting epithelial-mesenchymal transition (EMT) to enhance cancer invasiveness and growth, as well as stimulating cancer stem cell properties within the tumor. Moreover, CAFs can induce an immunosuppressive TME and contribute to therapeutic resistance. In this review, we summarize the fundamental knowledge and recent advances regarding CAFs, focusing on their sophisticated roles in cancer development and potential as therapeutic targets. We discuss various strategies to target CAFs, including ECM modulation, direct elimination, interruption of CAF-TME crosstalk, and CAF normalization, as approaches to developing more effective treatments. An improved understanding of the complex interplay between CAFs and TME is crucial for developing new and effective targeted therapies for cancer.
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Affiliation(s)
- Hongyuan Jia
- Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Xingmin Chen
- Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Linling Zhang
- Department of Respiratory and Critical Care, Chengdu Third People's Hospital, Chengdu, China
| | - Meihua Chen
- Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China.
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Jordan E, Arriaga MA, Obregon H, Villalobos V, Duarte MA, Garcia K, Levy A, Chew SA. Dual delivery of metformin and Y15 from a PLGA scaffold for the treatment of platinum-resistant ovarian cancer. Future Med Chem 2025; 17:301-312. [PMID: 39887289 PMCID: PMC11792864 DOI: 10.1080/17568919.2025.2458457] [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: 10/23/2024] [Accepted: 01/07/2025] [Indexed: 02/01/2025] Open
Abstract
AIMS Drug-loaded poly(lactic-co-glycolic acid) (PLGA) scaffolds were fabricated using a mold-less technique to investigate whether the combined delivery of both Y15 (FAK inhibitor) and metformin would result in enhanced effects on cell viability compared to the release of each drug alone for the treatment of platinum-resistant ovarian cancer (PROC). MATERIALS & METHODS Scaffolds were fabricated using an easy and economical mold-less technique that combined PLGA and the drugs (i.e. metformin and/or Y15) in tetraglycol and injected in PBS, to form a globular morphology. RESULTS The exposure of cells to metformin and Y15 resulted in a significantly enhanced cytotoxic efficacy compared to single-drug treatment with either metformin or Y15. When the drugs were delivered using the PLGA scaffolds, the combination of the two drugs was significantly more cytotoxic compared to scaffolds containing metformin only and Y15 only. CONCLUSIONS The combination of metformin and Y15 can result in an increase in antitumor activity in PROC cells through apoptosis. The delivery of both drugs from the PLGA biomaterial scaffold allowed for a more enhanced combinational effect compared to the utilization of free drugs (without a scaffold) and should be further explored as a promising treatment of PROC.
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Affiliation(s)
- Emily Jordan
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Marco A. Arriaga
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Hannah Obregon
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Viviana Villalobos
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Manuel A. Duarte
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Kristal Garcia
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
| | - Arkene Levy
- Dr Kiran C Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Sue Anne Chew
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, TX, USA
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Chang KS, Chen ST, Lin WY, Hsu SY, Sung HC, Lin YH, Feng TH, Hou CP, Juang HH. Growth differentiation factor 15 is a glucose-downregulated gene acting as the cross talk between stroma and cancer cells of the human bladder. Am J Physiol Cell Physiol 2025; 328:C557-C573. [PMID: 39804805 DOI: 10.1152/ajpcell.00230.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 12/17/2024] [Accepted: 12/17/2024] [Indexed: 01/16/2025]
Abstract
Hyperglycemia and hyperglycosuria, two primary characteristics of diabetes mellitus, may increase the risk of cancer initiation, particularly for bladder cancer. The effectiveness of metformin, a common antidiabetic agent, is determined by its ability to induce growth differentiation factor 15 (GDF15). However, the mechanism of the GDF15 in relation to glucose, which influences the tumor microenvironment in the human bladder, is not fully understood. This study explores the potential roles of GDF15 in response to glucose in the human bladder. High glucose treatment (30 mM) enhanced phosphorylation of AKT at S473 and AMP-activated protein kinase α1/2 (AMPKα1/2) at S485 to block the counteracting effect of metformin on the AMPK activity in bladder cancer and stroma [human bladder stromal fibroblast (HBdSF) and human bladder smooth muscle cell (HBdSMC)] cells compared with normal glucose treatment (5 mM). Metformin modulated the expressions of GDF15, NDRG1, Maspin, and epithelial-to-mesenchymal transition (EMT) markers to attenuate cell proliferation and invasion of bladder cancer cells. Caffeic acid phenethyl ester (CAPE), like metformin, behaves as an inducer of AMPK activity to stimulate GDF15 expression. Knockdown of GDF15 blocked the downregulation of CAPE on the contraction of HBdSMCs. Both CAPE-induced GDF15 expression and the supernatant from bladder cancer cells with overexpressing GDF15 impeded the HBdSF and HBdSMC migration, suggesting that CAPE-upregulated GDF15 blocked the cell migration. These findings reveal that high glucose treatment inhibits the counteracting effects of either metformin or CAPE on the AMPK activity and GDF15 is downregulated by glucose and induced by metformin and CAPE in both stroma and cancer cells. Furthermore, GDF15 is an antitumor gene facilitating communication between stroma and cancer cells in the human bladder.NEW & NOTEWORTHY This study investigates the counteraction of either CAPE or metformin with the AMPK activity increasing GDF15 expression in human bladder cells. The findings are the first study to indicate the secretion of GDF15 from cancer and stroma cells via autocrine or paracrine mechanisms. Our study suggests that GDF15, an antitumor gene in the human bladder induced by AMPK inducers, acts as a communication link between stroma and cancer cells in the human bladder.
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Affiliation(s)
- Kang-Shuo Chang
- Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Syue-Ting Chen
- Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Urology, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan
| | - Wei-Yin Lin
- Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan
| | - Shu-Yuan Hsu
- Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hsin-Ching Sung
- Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Hsiang Lin
- Department of Urology, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan
| | - Tsui-Hsia Feng
- School of Nursing, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chen-Pang Hou
- Department of Urology, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan
| | - Horng-Heng Juang
- Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Urology, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan
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Li Y, Jian J, Ge H, Gao X, Qiang J. Peritumoral MRI Radiomics Features Increase the Evaluation Efficiency for Response to Chemotherapy in Patients With Epithelial Ovarian Cancer. J Magn Reson Imaging 2024; 60:2718-2727. [PMID: 38517321 DOI: 10.1002/jmri.29359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 03/11/2024] [Accepted: 03/11/2024] [Indexed: 03/23/2024] Open
Abstract
BACKGROUND It remains unclear whether extracting peritumoral volume (PTV) radiomics features are useful tools for evaluating response to chemotherapy of epithelial ovarian cancer (EOC). PURPOSE To evaluate MRI radiomics signatures (RS) capturing subtle changes of PTV and their added evaluation performance to whole tumor volume (WTV) for response to chemotherapy in patients with EOC. STUDY TYPE Retrospective. POPULATION 219 patients aged from 15 to 79 years were enrolled. FIELD STRENGTH/SEQUENCE 3.0 or 1.5T, axial fat-suppressed T2-weighted imaging (FS-T2WI), diffusion-weighted imaging (DWI), and contrast enhanced T1-weighted imaging (CE-T1WI). ASSESSMENT MRI features were extracted from the four axial sequences and six different volumes of interest (VOIs) (WTV and WTV + PTV (WPTV)) with different peritumor sizes (PS) ranging from 1 to 5 mm. Those features underwent preprocessing, and the most informative features were selected using minimum redundancy maximum relevance and least absolute shrinkage and selection operator to construct the RS. The optimal RS, with the highest area under the curve (AUC) of receiver operating characteristic was then integrated with independent clinical characteristics through multivariable logistic regression to construct the radiomics-clinical model (RCM). STATISTICAL TESTS Mann-Whitney U test, chi-squared test, DeLong test, log-rank test. P < 0.05 indicated a significant difference. RESULTS All the RSs constructed on WPTV exhibited higher AUCs (0.720-0.756) than WTV (0.671). Of which, RS with PS = 2 mm displayed a significantly better performance (AUC = 0.756). International Federation of Gynecology and Obstetrics (FIGO) stage was identified as the exclusive independent clinical evaluation characteristic, and the RCM demonstrated higher AUC (0.790) than the RS, but without statistical significance (P = 0.261). DATA CONCLUSION The radiomics features extracted from PTV could increase the efficiency of WTV radiomics for evaluating the chemotherapy response of EOC. The cut-off of 2 mm PTV was a reasonable value to obtain effective evaluation efficiency. LEVEL OF EVIDENCE 4 TECHNICAL EFFICACY: Stage 2.
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Affiliation(s)
- Yong'ai Li
- Department of Radiology, Changzhi People's Hospital, Changzhi, Shanxi, China
- Department of Radiology, Jinshan Hospital, Fudan University, Shanghai, China
| | - Junming Jian
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu, China
| | - Huijie Ge
- Department of Radiology, Changzhi People's Hospital, Changzhi, Shanxi, China
| | - Xin Gao
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu, China
- Jinan Guoke Medical Engineering and Technology Development Co., Ltd., Jinan, Shandong, China
| | - Jinwei Qiang
- Department of Radiology, Jinshan Hospital, Fudan University, Shanghai, China
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Yu S, Wang S, Wang X, Xu X. The axis of tumor-associated macrophages, extracellular matrix proteins, and cancer-associated fibroblasts in oncogenesis. Cancer Cell Int 2024; 24:335. [PMID: 39375726 PMCID: PMC11459962 DOI: 10.1186/s12935-024-03518-8] [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: 02/22/2024] [Accepted: 09/29/2024] [Indexed: 10/09/2024] Open
Abstract
The extracellular matrix (ECM) is a complex, dynamic network of multiple macromolecules that serve as a crucial structural and physical scaffold for neighboring cells. In the tumor microenvironment (TME), ECM proteins play a significant role in mediating cellular communication between cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). Revealing the ECM modification of the TME necessitates the intricate signaling cascades that transpire among diverse cell populations and ECM proteins. The advent of single-cell sequencing has enabled the identification and refinement of specific cellular subpopulations, which has substantially enhanced our comprehension of the intricate milieu and given us a high-resolution perspective on the diversity of ECM proteins. However, it is essential to integrate single-cell data and establish a coherent framework. In this regard, we present a comprehensive review of the relationships among ECM, TAMs, and CAFs. This encompasses insights into the ECM proteins released by TAMs and CAFs, signaling integration in the TAM-ECM-CAF axis, and the potential applications and limitations of targeted therapies for CAFs. This review serves as a reliable resource for focused therapeutic strategies while highlighting the crucial role of ECM proteins as intermediates in the TME.
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Affiliation(s)
- Shuhong Yu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Siyu Wang
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Xuanyu Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Ximing Xu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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Hajimohammadebrahim-Ketabforoush M, Zali A, Shahmohammadi M, Hamidieh AA. Metformin and its potential influence on cell fate decision between apoptosis and senescence in cancer, with a special emphasis on glioblastoma. Front Oncol 2024; 14:1455492. [PMID: 39267853 PMCID: PMC11390356 DOI: 10.3389/fonc.2024.1455492] [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: 06/26/2024] [Accepted: 08/12/2024] [Indexed: 09/15/2024] Open
Abstract
Despite reaching enormous achievements in therapeutic approaches worldwide, GBM still remains the most incurable malignancy among various cancers. It emphasizes the necessity of adjuvant therapies from the perspectives of both patients and healthcare providers. Therefore, most emerging studies have focused on various complementary and adjuvant therapies. Among them, metabolic therapy has received special attention, and metformin has been considered as a treatment in various types of cancer, including GBM. It is clearly evident that reaching efficient approaches without a comprehensive evaluation of the key mechanisms is not possible. Among the studied mechanisms, one of the more challenging ones is the effect of metformin on apoptosis and senescence. Moreover, metformin is well known as an insulin sensitizer. However, if insulin signaling is facilitated in the tumor microenvironment, it may result in tumor growth. Therefore, to partially resolve some paradoxical issues, we conducted a narrative review of related studies to address the following questions as comprehensively as possible: 1) Does the improvement of cellular insulin function resulting from metformin have detrimental or beneficial effects on GBM cells? 2) If these effects are detrimental to GBM cells, which is more important: apoptosis or senescence? 3) What determines the cellular decision between apoptosis and senescence?
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Affiliation(s)
- Melika Hajimohammadebrahim-Ketabforoush
- Student Research Committee, Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Zali
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Shahmohammadi
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Ali Hamidieh
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Pratticò F, Garajová I. Focus on Pancreatic Cancer Microenvironment. Curr Oncol 2024; 31:4241-4260. [PMID: 39195299 PMCID: PMC11352508 DOI: 10.3390/curroncol31080316] [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: 06/16/2024] [Revised: 07/18/2024] [Accepted: 07/25/2024] [Indexed: 08/29/2024] Open
Abstract
Pancreatic ductal adenocarcinoma remains one of the most lethal solid tumors due to its local aggressiveness and metastatic potential, with a 5-year survival rate of only 13%. A robust connection between pancreatic cancer microenvironment and tumor progression exists, as well as resistance to current anticancer treatments. Pancreatic cancer has a complex tumor microenvironment, characterized by an intricate crosstalk between cancer cells, cancer-associated fibroblasts and immune cells. The complex composition of the tumor microenvironment is also reflected in the diversity of its acellular components, such as the extracellular matrix, cytokines, growth factors and secreted ligands involved in signaling pathways. Desmoplasia, the hallmark of the pancreatic cancer microenvironment, contributes by creating a dense and hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance and suppresses anti-tumor immune invasion. We discuss the complex crosstalk among tumor microenvironment components and explore therapeutic strategies and opportunities in pancreatic cancer research. Better understanding of the tumor microenvironment and its influence on pancreatic cancer progression could lead to potential novel therapeutic options, such as integration of immunotherapy and cytokine-targeted treatments.
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Affiliation(s)
| | - Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, 43100 Parma, Italy;
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Pu W, Ma C, Wang B, Zhu W, Chen H. The "Heater" of "Cold" Tumors-Blocking IL-6. Adv Biol (Weinh) 2024; 8:e2300587. [PMID: 38773937 DOI: 10.1002/adbi.202300587] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 03/13/2024] [Indexed: 05/24/2024]
Abstract
The resolution of inflammation is not simply the end of the inflammatory response but rather a complex process that involves various cells, inflammatory factors, and specialized proresolving mediators following the occurrence of inflammation. Once inflammation cannot be cleared by the body, malignant tumors may be induced. Among them, IL-6, as an immunosuppressive factor, activates a variety of signal transduction pathways and induces tumorigenesis. Monitoring IL-6 can be used for the diagnosis, efficacy evaluation and prognosis of tumor patients. In terms of treatment, improving the efficacy of targeted and immunotherapy remains a major challenge. Blocking IL-6 and its mediated signaling pathways can regulate the tumor immune microenvironment and enhance immunotherapy responses by activating immune cells. Even transform "cold" tumors that are difficult to respond to immunotherapy into immunogenic "hot" tumors, acting as a "heater" for "cold" tumors, restarting the tumor immune cycle, and reducing immunotherapy-related toxic reactions and drug resistance. In clinical practice, the combined application of IL-6 inhibition with targeted therapy and immunotherapy may produce synergistic results. Nevertheless, additional clinical trials are imperative to further validate the safety and efficacy of this therapeutic approach.
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Affiliation(s)
- Weigao Pu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730030, China
- Department of Tumour Surgery, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Chenhui Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730030, China
- Department of Tumour Surgery, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Bofang Wang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730030, China
- Department of Tumour Surgery, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Weidong Zhu
- General Surgery Department of Lintao County People's Hospital in Gansu Province, Lanzhou, Gansu, 730030, China
| | - Hao Chen
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730030, China
- Department of Tumour Surgery, Lanzhou University Second Hospital, Lanzhou, 730030, China
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou, Gansu, 730030, China
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Salminen A, Kaarniranta K, Kauppinen A. Tissue fibroblasts are versatile immune regulators: An evaluation of their impact on the aging process. Ageing Res Rev 2024; 97:102296. [PMID: 38588867 DOI: 10.1016/j.arr.2024.102296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 03/26/2024] [Accepted: 04/03/2024] [Indexed: 04/10/2024]
Abstract
Fibroblasts are abundant stromal cells which not only control the integrity of extracellular matrix (ECM) but also act as immune regulators. It is known that the structural cells within tissues can establish an organ-specific immunity expressing many immune-related genes and closely interact with immune cells. In fact, fibroblasts can modify their immune properties to display both pro-inflammatory and immunosuppressive activities in a context-dependent manner. After acute insults, fibroblasts promote tissue inflammation although they concurrently recruit immunosuppressive cells to enhance the resolution of inflammation. In chronic pathological states, tissue fibroblasts, especially senescent fibroblasts, can display many pro-inflammatory and immunosuppressive properties and stimulate the activities of different immunosuppressive cells. In return, immunosuppressive cells, such as M2 macrophages and myeloid-derived suppressor cells (MDSC), evoke an excessive conversion of fibroblasts into myofibroblasts, thus aggravating the severity of tissue fibrosis. Single-cell transcriptome studies on fibroblasts isolated from aged tissues have confirmed that tissue fibroblasts express many genes coding for cytokines, chemokines, and complement factors, whereas they lose some fibrogenic properties. The versatile immune properties of fibroblasts and their close cooperation with immune cells indicate that tissue fibroblasts have a crucial role in the aging process and age-related diseases.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, Kuopio FI-70211, Finland.
| | - Kai Kaarniranta
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, Kuopio FI-70211, Finland; Department of Ophthalmology, Kuopio University Hospital, P.O. Box 100, KYS FI-70029, Finland
| | - Anu Kauppinen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, Kuopio FI-70211, Finland
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Goglia U, Hasballa I, Teti C, Boschetti M, Ferone D, Albertelli M. Ianus Bifrons: The Two Faces of Metformin. Cancers (Basel) 2024; 16:1287. [PMID: 38610965 PMCID: PMC11011026 DOI: 10.3390/cancers16071287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/10/2024] [Accepted: 03/20/2024] [Indexed: 04/14/2024] Open
Abstract
The ancient Roman god Ianus was a mysterious divinity with two opposite faces, one looking at the past and the other looking to the future. Likewise, metformin is an "old" drug, with one side looking at the metabolic role and the other looking at the anti-proliferative mechanism; therefore, it represents a typical and ideal bridge between diabetes and cancer. Metformin (1,1-dimethylbiguanidine hydrochloride) is a drug that has long been in use for the treatment of type 2 diabetes mellitus, but recently evidence is growing about its potential use in other metabolic conditions and in proliferative-associated diseases. The aim of this paper is to retrace, from a historical perspective, the knowledge of this molecule, shedding light on the subcellular mechanisms of action involved in metabolism as well as cellular and tissue growth. The intra-tumoral pharmacodynamic effects of metformin and its possible role in the management of different neoplasms are evaluated and debated. The etymology of the name Ianus is probably from the Latin term ianua, which means door. How many new doors will this old drug be able to open?
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Affiliation(s)
- Umberto Goglia
- Endocrinology and Diabetology Unit, Local Health Authority CN1, 12100 Cuneo, Italy
| | - Iderina Hasballa
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy (M.B.); (D.F.); (M.A.)
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genoa, Italy
| | - Claudia Teti
- Endocrinology and Diabetology Unit, Local Health Autorithy Imperia 1, 18100 Imperia, Italy;
| | - Mara Boschetti
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy (M.B.); (D.F.); (M.A.)
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genoa, Italy
| | - Diego Ferone
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy (M.B.); (D.F.); (M.A.)
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genoa, Italy
| | - Manuela Albertelli
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy (M.B.); (D.F.); (M.A.)
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI), University of Genova, 16132 Genoa, Italy
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Meng X, Ma F, Yu D. The diverse effects of cisplatin on tumor microenvironment: Insights and challenges for the delivery of cisplatin by nanoparticles. ENVIRONMENTAL RESEARCH 2024; 240:117362. [PMID: 37827371 DOI: 10.1016/j.envres.2023.117362] [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: 07/16/2023] [Revised: 09/11/2023] [Accepted: 10/09/2023] [Indexed: 10/14/2023]
Abstract
Cisplatin is a well-known platinum-based chemotherapy medication that is widely utilized for some malignancies. Despite the direct cytotoxic consequences of cisplatin on tumor cells, studies in the recent decade have revealed that cisplatin can also affect different cells and their secretions in the tumor microenvironment (TME). Cisplatin has complex impacts on the TME, which may contribute to its anti-tumor activity or drug resistance mechanisms. These regulatory effects of cisplatin play a paramount function in tumor growth, invasion, and metastasis. This paper aims to review the diverse impacts of cisplatin and nanoparticles loaded with cisplatin on cancer cells and also non-cancerous cells in TME. The impacts of cisplatin on immune cells, tumor stroma, cancer cells, and also hypoxia will be discussed in the current review. Furthermore, we emphasize the challenges and prospects of using cisplatin in combination with other adjuvants and therapeutic modalities that target TME. We also discuss the potential synergistic effects of cisplatin with immune checkpoint inhibitors (ICIs) and other agents with anticancer potentials such as polyphenols and photosensitizers. Furthermore, the potential of nanoparticles for targeting TME and better delivery of cisplatin into tumors will be discussed.
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Affiliation(s)
- Xinxin Meng
- Zhuji Sixth People's Hospital of Zhejiang Province, Zhuji, Zhejiang, 311801, China
| | - Fengyun Ma
- Zhuji People's Hospital of Zhejiang Province, Zhuji Affiliated Hospital of Shaoxing University, Zhuji, Zhejiang, 311800, China.
| | - Dingli Yu
- Zhuji People's Hospital of Zhejiang Province, Zhuji Affiliated Hospital of Shaoxing University, Zhuji, Zhejiang, 311800, China
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13
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Gupta J, Jalil AT, Abd Alzahraa ZH, Aminov Z, Alsaikhan F, Ramírez-Coronel AA, Ramaiah P, Najafi M. The Metformin Immunoregulatory Actions in Tumor Suppression and Normal Tissues Protection. Curr Med Chem 2024; 31:5370-5396. [PMID: 37403391 DOI: 10.2174/0929867331666230703143907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/19/2023] [Accepted: 06/01/2023] [Indexed: 07/06/2023]
Abstract
The immune system is the key player in a wide range of responses in normal tissues and tumors to anticancer therapy. Inflammatory and fibrotic responses in normal tissues are the main limitations of chemotherapy, radiotherapy, and also some newer anticancer drugs such as immune checkpoint inhibitors (ICIs). Immune system responses within solid tumors including anti-tumor and tumor-promoting responses can suppress or help tumor growth. Thus, modulation of immune cells and their secretions such as cytokines, growth factors and epigenetic modulators, pro-apoptosis molecules, and some other molecules can be suggested to alleviate side effects in normal tissues and drug-resistance mechanisms in the tumor. Metformin as an anti-diabetes drug has shown intriguing properties such as anti-inflammation, anti-fibrosis, and anticancer effects. Some investigations have uncovered that metformin can ameliorate radiation/chemotherapy toxicity in normal cells and tissues through the modulation of several targets in cells and tissues. These effects of metformin may ameliorate severe inflammatory responses and fibrosis after exposure to ionizing radiation or following treatment with highly toxic chemotherapy drugs. Metformin can suppress the activity of immunosuppressive cells in the tumor through the phosphorylation of AMP-activated protein kinase (AMPK). In addition, metformin may stimulate antigen presentation and maturation of anticancer immune cells, which lead to the induction of anticancer immunity in the tumor. This review aims to explain the detailed mechanisms of normal tissue sparing and tumor suppression during cancer therapy using adjuvant metformin with an emphasis on immune system responses.
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Affiliation(s)
- Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura, Pin Code 281406, U. P., India
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq
| | | | - Zafar Aminov
- Department of Public Health and Healthcare management, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan
- Department of Scientific Affairs, Tashkent State Dental Institute, 103 Makhtumkuli Str., Tashkent, Uzbekistan
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia
| | - Andrés Alexis Ramírez-Coronel
- Azogues Campus Nursing Career, Health and Behavior Research Group (HBR), Psychometry and Ethology Laboratory, Catholic University of Cuenca, Cuenca, Ecuador
- Epidemiology and Biostatistics Research Group, CES University, Medellin, Colombia
- Educational Statistics Research Group (GIEE), National University of Education, Cuenca, Ecuador
| | | | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
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14
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Chiu CH, Lin YJ, Ramesh S, Kuo WW, Chen MC, Kuo CH, Li CC, Wang TF, Lin YM, Liao PH, Huang CY. Gemcitabine resistance in non-small cell lung cancer is mediated through activation of the PI3K/AKT/NF-κB pathway and suppression of ERK signaling by reactive oxygen species. J Biochem Mol Toxicol 2023; 37:e23497. [PMID: 37564025 DOI: 10.1002/jbt.23497] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 07/20/2023] [Accepted: 07/31/2023] [Indexed: 08/12/2023]
Abstract
Lung cancer is one of the most common cancers in the world. Chemotherapy is a standard clinical treatment. However, tumor cells often develop multidrug resistance after chemotherapy, an inevitable bottleneck in cancer treatment. Therefore, this study used gemcitabine-resistant (GEM-R) CL1-0 lung cancer cells. First, we used flow cytometry and western blot analysis to examine differences in performance between resistant and parental cells. The results showed that compared with parental cells, GEM-R CL1-0 cells significantly enhanced the activation of the AKT pathway, which promoted survival and growth, and decreased the activation of the reactive oxygen species-extracellular signal-regulated kinase (ROS)-ERK pathway. Next, the AKT and ERK pathways' role in tumor growth was further explored in vivo using a xenograft model. The results showed that enhancing AKT and inhibiting ERK activation reduced GEM-induced inhibition of tumor growth. Finally, combining the above results, we found that GEM-R CL1-0 cells showed reduced sensitivity to GEM by activating the phosphatidylinositol 3-kinase/AKT/NF-kB pathway and inhibiting the ROS-ERK pathway leading to resistance against GEM. Therefore, the AKT and ERK pathways are potential targets for improving the sensitivity of cancer cells to anticancer drugs.
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Affiliation(s)
- Chih-Hao Chiu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Yu-Jung Lin
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- School of Post-Baccalaureate Chinese Medicine, College of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Samiraj Ramesh
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Department of Research and Innovation, Institute of Biotechnology, Saveetha School of Engineering (SSE), Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, India
| | - Wei-Wen Kuo
- Department of Biological Science and Technology, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung, Taiwan
| | - Ming-Cheng Chen
- Division of Colorectal Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
- Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chia-Hua Kuo
- Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan
| | - Chi-Cheng Li
- Center of Stem Cell & Precision Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Tso-Fu Wang
- Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Yueh-Min Lin
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
- Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
| | - Po-Hsiang Liao
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Chih-Yang Huang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
- Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan
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15
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Tajaldini M, Poorkhani A, Amiriani T, Amiriani A, Javid H, Aref P, Ahmadi F, Sadani S, Khori V. Strategy of targeting the tumor microenvironment via inhibition of fibroblast/fibrosis remodeling new era to cancer chemo-immunotherapy resistance. Eur J Pharmacol 2023; 957:175991. [PMID: 37619785 DOI: 10.1016/j.ejphar.2023.175991] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 08/02/2023] [Accepted: 08/10/2023] [Indexed: 08/26/2023]
Abstract
The use of repurposing drugs that may have neoplastic and anticancer effects increases the efficiency and decrease resistance to chemotherapy drugs through a biochemical and mechanical transduction mechanisms through modulation of fibroblast/fibrosis remodeling in tumor microenvironment (TME). Interestingly, fibroblast/fibrosis remodeling plays a vital role in mediating cancer metastasis and drug resistance after immune chemotherapy. The most essential hypothesis for induction of chemo-immunotherapy resistance is via activation of fibroblast/fibrosis remodeling and preventing the infiltration of T cells after is mainly due to the interference between cytoskeleton, mechanical, biochemical, metabolic, vascular, and remodeling signaling pathways in TME. The structural components of the tumor that can be targeted in the fibroblast/fibrosis remodeling include the depletion of the TME components, targeting the cancer-associated fibroblasts and tumor associated macrophages, alleviating the mechanical stress within the ECM, and normalizing the blood vessels. It has also been found that during immune-chemotherapy, TME injury and fibroblast/fibrosis remodeling causes the up-regulation of inhibitory signals and down-regulation of activated signals, which results in immune escape or chemo-resistance of the tumor. In this regard, repurposing or neo-adjuvant drugs with various transduction signaling mechanisms, including anti-fibrotic effects, are used to target the TME and fibroblast/fibrosis signaling pathway such as angiotensin 2, transforming growth factor-beta, physical barriers of the TME, cytokines and metabolic factors which finally led to the reverse of the chemo-resistance. Consistent to many repurposing drugs such as pirfenidone, metformin, losartan, tranilast, dexamethasone and pentoxifylline are used to decrease immune-suppression by abrogation of TME inhibitory signal that stimulates the immune system and increases efficiency and reduces resistance to chemotherapy drugs. To overcome immunosuppression based on fibroblast/fibrosis remodeling, in this review, we focus on inhibitory signal transduction, which is the physical barrier, alleviates mechanical stress and prevents mechano-metabolic activation.
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Affiliation(s)
- Mahboubeh Tajaldini
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Amirhoushang Poorkhani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Taghi Amiriani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Amirhossein Amiriani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciencess, Catastega Institue of Medical Sciences, Mashhad, Iran
| | - Parham Aref
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Farahnazsadat Ahmadi
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Somayeh Sadani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
| | - Vahid Khori
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
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16
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Yan J, Xu F, Zhou D, Zhang S, Zhang B, Meng Q, Lv Q. Metabolic reprogramming of three major nutrients in platinum-resistant ovarian cancer. Front Oncol 2023; 13:1231460. [PMID: 37681030 PMCID: PMC10482409 DOI: 10.3389/fonc.2023.1231460] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 08/08/2023] [Indexed: 09/09/2023] Open
Abstract
Metabolic reprogramming is a phenomenon in which cancer cells alter their metabolic pathways to support their uncontrolled growth and survival. Platinum-based chemotherapy resistance is associated with changes in glucose metabolism, amino acid metabolism, fatty acid metabolism, and tricarboxylic acid cycle. These changes lead to the creation of metabolic intermediates that can provide precursors for the biosynthesis of cellular components and help maintain cellular energy homeostasis. This article reviews the research progress of the metabolic reprogramming mechanism of platinumbased chemotherapy resistance caused by three major nutrients in ovarian cancer.
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Affiliation(s)
- Jinbowen Yan
- Department of Obstetrics and Gynecology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Fangzhi Xu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital, National Center of Gerontology of National Health Commission, Beijing, China
| | - Dan Zhou
- Department of Obstetrics and Gynecology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Shuo Zhang
- Department of Obstetrics and Gynecology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Bo Zhang
- Department of Obstetrics and Gynecology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Qingwei Meng
- Department of Obstetrics and Gynecology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Qiubo Lv
- Department of Obstetrics and Gynecology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
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17
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Karmokar PF, Moniri NH. Free-fatty acid receptor-1 (FFA1/GPR40) promotes papillary RCC proliferation and tumor growth via Src/PI3K/AKT/NF-κB but suppresses migration by inhibition of EGFR, ERK1/2, STAT3 and EMT. Cancer Cell Int 2023; 23:126. [PMID: 37355607 DOI: 10.1186/s12935-023-02967-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 06/07/2023] [Indexed: 06/26/2023] Open
Abstract
BACKGROUND Papillary renal cell carcinoma (pRCC) is a highly metastatic genitourinary cancer and is generally irresponsive to common treatments used for the more prevalent clear-cell (ccRCC) subtype. The goal of this study was to examine the novel role of the free fatty-acid receptor-1 (FFA1/GPR40), a cell-surface expressed G protein-coupled receptor that is activated by medium-to-long chained dietary fats, in modulation of pRCC cell migration invasion, proliferation and tumor growth. METHODS We assessed the expression of FFA1 in human pRCC and ccRCC tumor tissues compared to patient-matched non-cancerous controls, as well as in RCC cell lines. Using the selective FFA1 agonist AS2034178 and the selective FFA1 antagonist GW1100, we examined the role of FFA1 in modulating cell migration, invasion, proliferation and tumor growth and assessed the FFA1-associated intracellular signaling mechanisms via immunoblotting. RESULTS We reveal for the first time that FFA1 is upregulated in pRCC tissue compared to patient-matched non-cancerous adjacent tissue and that its expression increases with pRCC cancer pathology, while the inverse is seen in ccRCC tissue. We also show that FFA1 is expressed in the pRCC cell line ACHN, but not in ccRCC cell lines, suggesting a unique role in pRCC pathology. Our results demonstrate that FFA1 agonism promotes tumor growth and cell proliferation via c-Src/PI3K/AKT/NF-κB and COX-2 signaling. At the same time, agonism of FFA1 strongly inhibits migration and invasion, which are mechanistically mediated via inhibition of EGFR, ERK1/2 and regulators of epithelial-mesenchymal transition. CONCLUSIONS Our data suggest that FFA1 plays oppositional growth and migratory roles in pRCC and identifies this receptor as a potential target for modulation of pathogenesis of this aggressive cancer.
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Affiliation(s)
- Priyanka F Karmokar
- Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University Health Sciences Center, Mercer University, 3001, Mercer University Drive, Atlanta, GA, 30341, USA
| | - Nader H Moniri
- Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University Health Sciences Center, Mercer University, 3001, Mercer University Drive, Atlanta, GA, 30341, USA.
- Department of Biomedical Sciences, School of Medicine, Mercer University Health Sciences Center, Mercer University, Macon, GA, 31207, USA.
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18
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Gutknecht da Silva JL, Passos DF, Cabral FL, Miron VV, Schetinger MRC, Cardoso AA, Dal Piva CH, Gomes CO, Ebone RS, Leal DBR. Istradefylline induces A2A/P2X7 crosstalk expression inducing pro-inflammatory signal, and reduces AKT/mTOR signaling in melanoma-bearing mice. Med Oncol 2023; 40:178. [PMID: 37188995 DOI: 10.1007/s12032-023-02033-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 04/15/2023] [Indexed: 05/17/2023]
Abstract
ATP and adenosine (ADO) are critical players in the context of cancer. In the tumor microenvironment, the signaling dependent on these molecules, and immune cells, is regulated by an enzymatic chain and purinergic receptors called purinome. Primarily, the A2A receptor (A2AR) has a pro-tumor action since it reduces the immune response and favors the growth of malignant melanoma. Therefore, this study aimed to verify the effects of A2AR antagonism with Istradefylline (IST) on the purinergic signaling profile of the melanoma tumor and immunological compartments. We observed reduced tumor growth of melanoma in IST-treated animals. IST inhibited AKT/mTOR pathway, which is involved with tumor growth. In the tumor, spleen, and thymus, the modulation of purinergic enzymes (CD39, CD73, and E-ADA) characterized a pro-inflammatory profile since it favored increased extracellular concentrations of ATP to the detriment of ADO. A2AR inhibition generated a compensatory feedback process with increased A2AR expression at the tumor level. However, there was also an increase in the expression of the P2X7 receptor (P2X7R), which culminated in an increase in pro-inflammatory pathways with the release of IL-1β and pro-inflammatory cytokines such as IFN-γ and TNF-α. Our data evidence the cross-involvement between expression and action of the A2AR and P2X7R. We suggest that IST is a promising drug for off-label use in cancer since it promotes an anti-tumoral response by producing pro-inflammatory cytokines and blocking of AKT/mTOR tumor growth pathway.
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Affiliation(s)
- Jean L Gutknecht da Silva
- Laboratório de Imunobiologia Experimental e Aplicada (LABIBIO), Departamento de Microbiologia e Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
- Programa de Pós-Graduação em Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Daniela F Passos
- Laboratório de Imunobiologia Experimental e Aplicada (LABIBIO), Departamento de Microbiologia e Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Fernanda L Cabral
- Laboratório de Imunobiologia Experimental e Aplicada (LABIBIO), Departamento de Microbiologia e Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Vanessa V Miron
- Programa de Pós-Graduação em Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Maria R C Schetinger
- Programa de Pós-Graduação em Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Andrieli A Cardoso
- Laboratório de Imunobiologia Experimental e Aplicada (LABIBIO), Departamento de Microbiologia e Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Camile H Dal Piva
- Laboratório de Imunobiologia Experimental e Aplicada (LABIBIO), Departamento de Microbiologia e Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Carolina O Gomes
- Laboratório de Imunobiologia Experimental e Aplicada (LABIBIO), Departamento de Microbiologia e Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Renan S Ebone
- Laboratório de Imunobiologia Experimental e Aplicada (LABIBIO), Departamento de Microbiologia e Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Daniela B R Leal
- Laboratório de Imunobiologia Experimental e Aplicada (LABIBIO), Departamento de Microbiologia e Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
- Programa de Pós-Graduação em Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
- Departamento de Microbiologia e Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Av. Roraima, 1000, Prédio 20, Santa Maria, RS, 97105-900, Brazil.
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19
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Chhabra Y, Weeraratna AT. Fibroblasts in cancer: Unity in heterogeneity. Cell 2023; 186:1580-1609. [PMID: 37059066 PMCID: PMC11422789 DOI: 10.1016/j.cell.2023.03.016] [Citation(s) in RCA: 181] [Impact Index Per Article: 90.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/13/2023] [Accepted: 03/15/2023] [Indexed: 04/16/2023]
Abstract
Tumor cells do not exist in isolation in vivo, and carcinogenesis depends on the surrounding tumor microenvironment (TME), composed of a myriad of cell types and biophysical and biochemical components. Fibroblasts are integral in maintaining tissue homeostasis. However, even before a tumor develops, pro-tumorigenic fibroblasts in close proximity can provide the fertile 'soil' to the cancer 'seed' and are known as cancer-associated fibroblasts (CAFs). In response to intrinsic and extrinsic stressors, CAFs reorganize the TME enabling metastasis, therapeutic resistance, dormancy and reactivation by secreting cellular and acellular factors. In this review, we summarize the recent discoveries on CAF-mediated cancer progression with a particular focus on fibroblast heterogeneity and plasticity.
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Affiliation(s)
- Yash Chhabra
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Department of Oncology, Sidney Kimmel Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
| | - Ashani T Weeraratna
- Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Department of Oncology, Sidney Kimmel Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
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20
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Hyroššová P, Milošević M, Škoda J, Vachtenheim Jr J, Rohlena J, Rohlenová K. Effects of metabolic cancer therapy on tumor microenvironment. Front Oncol 2022; 12:1046630. [PMID: 36582801 PMCID: PMC9793001 DOI: 10.3389/fonc.2022.1046630] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 11/28/2022] [Indexed: 12/15/2022] Open
Abstract
Targeting tumor metabolism for cancer therapy is an old strategy. In fact, historically the first effective cancer therapeutics were directed at nucleotide metabolism. The spectrum of metabolic drugs considered in cancer increases rapidly - clinical trials are in progress for agents directed at glycolysis, oxidative phosphorylation, glutaminolysis and several others. These pathways are essential for cancer cell proliferation and redox homeostasis, but are also required, to various degrees, in other cell types present in the tumor microenvironment, including immune cells, endothelial cells and fibroblasts. How metabolism-targeted treatments impact these tumor-associated cell types is not fully understood, even though their response may co-determine the overall effectivity of therapy. Indeed, the metabolic dependencies of stromal cells have been overlooked for a long time. Therefore, it is important that metabolic therapy is considered in the context of tumor microenvironment, as understanding the metabolic vulnerabilities of both cancer and stromal cells can guide new treatment concepts and help better understand treatment resistance. In this review we discuss recent findings covering the impact of metabolic interventions on cellular components of the tumor microenvironment and their implications for metabolic cancer therapy.
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Affiliation(s)
- Petra Hyroššová
- Institute of Biotechnology of the Czech Academy of Sciences, Prague, Czechia
| | - Mirko Milošević
- Institute of Biotechnology of the Czech Academy of Sciences, Prague, Czechia
- Faculty of Science, Charles University, Prague, Czechia
| | - Josef Škoda
- Institute of Biotechnology of the Czech Academy of Sciences, Prague, Czechia
| | - Jiří Vachtenheim Jr
- 3rd Department of Surgery, First Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia
| | - Jakub Rohlena
- Institute of Biotechnology of the Czech Academy of Sciences, Prague, Czechia
| | - Kateřina Rohlenová
- Institute of Biotechnology of the Czech Academy of Sciences, Prague, Czechia
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21
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Sollazzo M, De Luise M, Lemma S, Bressi L, Iorio M, Miglietta S, Milioni S, Kurelac I, Iommarini L, Gasparre G, Porcelli AM. Respiratory Complex I dysfunction in cancer: from a maze of cellular adaptive responses to potential therapeutic strategies. FEBS J 2022; 289:8003-8019. [PMID: 34606156 PMCID: PMC10078660 DOI: 10.1111/febs.16218] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 09/03/2021] [Accepted: 10/01/2021] [Indexed: 01/14/2023]
Abstract
Mitochondria act as key organelles in cellular bioenergetics and biosynthetic processes producing signals that regulate different molecular networks for proliferation and cell death. This ability is also preserved in pathologic contexts such as tumorigenesis, during which bioenergetic changes and metabolic reprogramming confer flexibility favoring cancer cell survival in a hostile microenvironment. Although different studies epitomize mitochondrial dysfunction as a protumorigenic hit, genetic ablation or pharmacological inhibition of respiratory complex I causing a severe impairment is associated with a low-proliferative phenotype. In this scenario, it must be considered that despite the initial delay in growth, cancer cells may become able to resume proliferation exploiting molecular mechanisms to overcome growth arrest. Here, we highlight the current knowledge on molecular responses activated by complex I-defective cancer cells to bypass physiological control systems and to re-adapt their fitness during microenvironment changes. Such adaptive mechanisms could reveal possible novel molecular players in synthetic lethality with complex I impairment, thus providing new synergistic strategies for mitochondrial-based anticancer therapy.
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Affiliation(s)
- Manuela Sollazzo
- Department of Pharmacy and Biotechnology (FABIT), Alma Mater Studiorum-University of Bologna, Bologna, Italy.,Center for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy
| | - Monica De Luise
- Center for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Silvia Lemma
- Center for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Licia Bressi
- Center for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Maria Iorio
- Center for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Stefano Miglietta
- Department of Pharmacy and Biotechnology (FABIT), Alma Mater Studiorum-University of Bologna, Bologna, Italy.,Center for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy
| | - Sara Milioni
- Department of Pharmacy and Biotechnology (FABIT), Alma Mater Studiorum-University of Bologna, Bologna, Italy.,Center for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy
| | - Ivana Kurelac
- Center for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, Bologna, Italy.,Centro di Studio e Ricerca sulle Neoplasie (CSR) Ginecologiche, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Luisa Iommarini
- Department of Pharmacy and Biotechnology (FABIT), Alma Mater Studiorum-University of Bologna, Bologna, Italy.,Center for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy.,Centro di Studio e Ricerca sulle Neoplasie (CSR) Ginecologiche, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Giuseppe Gasparre
- Center for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, Bologna, Italy.,Centro di Studio e Ricerca sulle Neoplasie (CSR) Ginecologiche, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Anna Maria Porcelli
- Department of Pharmacy and Biotechnology (FABIT), Alma Mater Studiorum-University of Bologna, Bologna, Italy.,Center for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy.,Centro di Studio e Ricerca sulle Neoplasie (CSR) Ginecologiche, Alma Mater Studiorum-University of Bologna, Bologna, Italy.,Interdepartmental Center for Industrial Research (CIRI) Life Sciences and Technologies for Health, Alma Mater Studiorum-University of Bologna, Ozzano dell'Emilia, Italy
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22
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Mostafavi S, Zalpoor H, Hassan ZM. The promising therapeutic effects of metformin on metabolic reprogramming of cancer-associated fibroblasts in solid tumors. Cell Mol Biol Lett 2022; 27:58. [PMID: 35869449 PMCID: PMC9308248 DOI: 10.1186/s11658-022-00356-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 06/22/2022] [Indexed: 12/12/2022] Open
Abstract
Tumor-infiltrated lymphocytes are exposed to many toxic metabolites and molecules in the tumor microenvironment (TME) that suppress their anti-tumor activity. Toxic metabolites, such as lactate and ketone bodies, are produced mainly by catabolic cancer-associated fibroblasts (CAFs) to feed anabolic cancer cells. These catabolic and anabolic cells make a metabolic compartment through which high-energy metabolites like lactate can be transferred via the monocarboxylate transporter channel 4. Moreover, a decrease in molecules, including caveolin-1, has been reported to cause deep metabolic changes in normal fibroblasts toward myofibroblast differentiation. In this context, metformin is a promising drug in cancer therapy due to its effect on oncogenic signal transduction pathways, leading to the inhibition of tumor proliferation and downregulation of key oncometabolites like lactate and succinate. The cross-feeding and metabolic coupling of CAFs and tumor cells are also affected by metformin. Therefore, the importance of metabolic reprogramming of stromal cells and also the pivotal effects of metformin on TME and oncometabolites signaling pathways have been reviewed in this study.
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23
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Tossetta G. Metformin Improves Ovarian Cancer Sensitivity to Paclitaxel and Platinum-Based Drugs: A Review of In Vitro Findings. Int J Mol Sci 2022; 23:12893. [PMID: 36361682 PMCID: PMC9654053 DOI: 10.3390/ijms232112893] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/19/2022] [Accepted: 10/21/2022] [Indexed: 07/30/2023] Open
Abstract
Ovarian cancer is one of the most dangerous gynecologic cancers worldwide, showing a high fatality rate and recurrence due to diagnosis at an advanced stage of the disease and the occurrence of chemoresistance, which weakens the therapeutic effects of the chemotherapeutic treatments. In fact, although paclitaxel and platinum-based drugs (carboplatin or cisplatin) are widely used alone or in combination to treat ovarian cancer, the occurrence of chemoresistance significantly reduces the effects of these drugs. Metformin is a hypoglycemic agent that is commonly used for the treatment of type 2 diabetes mellitus and non-alcoholic fatty liver disease. However, this drug also shows anti-tumor activity, reducing cancer risk and chemoresistance. This review analyzes the current literature regarding the role of metformin in ovarian cancer and investigates what is currently known about its effects in reducing paclitaxel and platinum resistance to restore sensitivity to these drugs.
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Affiliation(s)
- Giovanni Tossetta
- Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, 60126 Ancona, Italy; ; Tel.: +39-0712206270
- Clinic of Obstetrics and Gynaecology, Department of Clinical Sciences, Università Politecnica delle Marche, Salesi Hospital, Azienda Ospedaliero Universitaria, 60126 Ancona, Italy
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24
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Jurj A, Ionescu C, Berindan-Neagoe I, Braicu C. The extracellular matrix alteration, implication in modulation of drug resistance mechanism: friends or foes? J Exp Clin Cancer Res 2022; 41:276. [PMID: 36114508 PMCID: PMC9479349 DOI: 10.1186/s13046-022-02484-1] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 09/01/2022] [Indexed: 11/10/2022] Open
Abstract
The extracellular matrix (ECM) is an important component of the tumor microenvironment (TME), having several important roles related to the hallmarks of cancer. In cancer, multiple components of the ECM have been shown to be altered. Although most of these alterations are represented by the increased or decreased quantity of the ECM components, changes regarding the functional alteration of a particular ECM component or of the ECM as a whole have been described. These alterations can be induced by the cancer cells directly or by the TME cells, with cancer-associated fibroblasts being of particular interest in this regard. Because the ECM has this wide array of functions in the tumor, preclinical and clinical studies have assessed the possibility of targeting the ECM, with some of them showing encouraging results. In the present review, we will highlight the most relevant ECM components presenting a comprehensive description of their physical, cellular and molecular properties which can alter the therapy response of the tumor cells. Lastly, some evidences regarding important biological processes were discussed, offering a more detailed understanding of how to modulate altered signalling pathways and to counteract drug resistance mechanisms in tumor cells.
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Affiliation(s)
- Ancuta Jurj
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, 400337, Cluj-Napoca, Romania
| | - Calin Ionescu
- 7Th Surgical Department, Iuliu Hațieganu University of Medicine and Pharmacy, 8 Victor Babes Street, 400012, Cluj-Napoca, Romania
- Surgical Department, Municipal Hospital, 400139, Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, 400337, Cluj-Napoca, Romania.
| | - Cornelia Braicu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hațieganu University of Medicine and Pharmacy, 400337, Cluj-Napoca, Romania.
- Research Center for Oncopathology and Translational Medicine (CCOMT), George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, 540139, Targu Mures, Romania.
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25
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Tsao SY. Potential of mRNA vaccines to become versatile cancer vaccines. World J Clin Oncol 2022; 13:663-674. [PMID: 36160466 PMCID: PMC9476609 DOI: 10.5306/wjco.v13.i8.663] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 06/15/2022] [Accepted: 07/25/2022] [Indexed: 02/06/2023] Open
Abstract
For centuries, therapeutic cancer vaccines have been developed and tried clinically. Way back in the late 19th century, the Father of Immunotherapy, William Coley had discovered that bacterial toxins were effective for inoperable sarcomas. In the 1970s, the Bacillus Calmette-Guérin (BCG) vaccine was repurposed, e.g., for advanced melanomas. Then, therapeutic cancer vaccines based on tumor-associated antigens (found on the surfaces of cancer cells) were tried clinically but apparently have not made a really significant clinical impact. For repurposed pathogen vaccines, only the BCG vaccine was approved in 1989 for local application to treat nonmuscle-invading bladder cancers. Although the mildly toxic vaccine adjuvants deliberately added to conventional pathogen vaccines are appropriate for seasonal applications, when repurposed for continual oncology usage, toxicity may be problematic. In 2010, even with the approval of sipuleucel-T as the very first cancer vaccine (dendritic cell) developed for designated prostate cancers, it has also not made a really significant clinical impact. Perhaps more "user friendly" cancer vaccines should be explored. As from approximately 30 years ago, the safety and effectiveness of mRNA vaccination for oncology had already been studied, the current coronavirus disease 2019 pandemic, though disastrous, has given such progressively advancing technology a kickstart. For oncology, other virtues of mRNA vaccines seem advantageous, e.g., rapid and versatile development, convenient modular design, and entirely cell-free synthesis, are being progressively recognized. Moreover, mRNAs encoding various oncology antigens for vaccination may also be tested with the combi-nation of relatively non-toxic modalities of oncology treatments, e.g., metformin or metronomic (low-dose, prolonged administration) chemotherapy. Admittedly, robust clinical data obtained through good quality clinical trials are mandatory.
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Affiliation(s)
- Shiu-Ying Tsao
- Department of Oncology, Hong Kong SAR Oncology Centre, Hong Kong SAR 999077, China
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26
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Кузнецов КО, Сафина ЭР, Гаймакова ДВ, Фролова ЯС, Оганесян ИЮ, Садертдинова АГ, Назмиева КА, Исламгулов АХ, Каримова АР, Галимова АМ, Ризванова ЭВ. [Metformin and malignant neoplasms: a possible mechanism of antitumor action and prospects for use in practice]. PROBLEMY ENDOKRINOLOGII 2022; 68:45-55. [PMID: 36337018 PMCID: PMC9762452 DOI: 10.14341/probl13097] [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: 04/08/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 06/16/2023]
Abstract
Metformin is a first-line antidiabetic drug for the treatment of type 2 diabetes mellitus (DM2); its molecular target is AMP-activated protein kinase (AMPK), which is involved in many metabolic processes. Metformin not only reduces blood glucose levels and improves insulin sensitivity, but also inhibits lipolysis and reduces cardiovascular risk in patients with DM2. In recent years, it has been proven that metformin slows down the aging process, stimulates hair growth, eliminates cognitive impairment, and also has an antitumor effect. Most basic studies have shown that metformin inhibits the growth of tumor cells and promotes cellular apoptosis, while clinical studies show contradictory results. This discrepancy can be explained by the difference in the concentration of metformin between basic and clinical studies. The maximum daily dose of metformin for patients with DM2 is 2500 mg / day, and the dose used in basic research was much higher. Metformin directly activates the AMPK signaling pathway, inhibits the production of reactive oxygen species, induces the activation of mTORC1, inhibits cyclin D1, which leads to a reduction in the risk of the occurrence and development of malignant neoplasms. In addition, metformin indirectly inhibits tumor growth, proliferation, invasion and metastasis by reducing the concentration of glucose in the blood, insulin resistance, as well as by reducing inflammation and affecting the tumor microenvironment. Glycolysis plays an important role in the energy metabolism of tumors, and metformin is able to have an inhibitory effect on it. Currently, studies of the mechanism of antitumor effects of metformin are becoming more extensive and in-depth, but there are still some contradictions.
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Affiliation(s)
- К. О. Кузнецов
- Российский национальный исследовательский медицинский университет им. Н.И. Пирогова
| | - Э. Р. Сафина
- Башкирский государственный медицинский университет
| | | | - Я. С. Фролова
- Первый Московский государственный медицинский университет им. И.М. Сеченова
| | - И. Ю. Оганесян
- Первый Московский государственный медицинский университет им. И.М. Сеченова
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27
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Angre T, Kumar A, Singh AK, Thareja S, Kumar P. Role of collagen regulators in cancer treatment: A comprehensive review. Anticancer Agents Med Chem 2022; 22:2956-2984. [DOI: 10.2174/1871520622666220501162351] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/13/2022] [Accepted: 03/25/2022] [Indexed: 12/24/2022]
Abstract
Abstract:
Collagen is the most important structural protein and also a main component of extra-cellular matrix (ECM). It plays a role in tumor progression. Collagen can be regulated by altering it’s biosynthesis pathway through various signaling pathways, receptors and genes. Activity of cancer cells can also be regulated by other ECM components like metalloproteinases, hyaluronic acid, fibronectin and so on. Hypoxia is also one of the condition which leads to cancer progression by stimulating the expression of procollagen lysine as a collagen crosslinker, which increases the size of collagen fibres promoting cancer spread. The collagen content in cancerous cells leads to resistance in chemotherapy. So, to reduce this resistance, some of the collagen regulating therapies are introduced, which include inhibiting its biosynthesis, disturbing cancer cell signaling pathway, mediating ECM components and directly utilizing collagenase. This study is an effort to compile the strategies reported to control the collagen level and different collagen inhibitors reported so far. More research is needed in this area, growing understandings of collagen’s structural features and its role in cancer progression will aid in the advancement of newer chemotherapies.
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Affiliation(s)
- Tanuja Angre
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, India
| | - Adarsh Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, India
| | - Ankit Kumar Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, India
| | - Suresh Thareja
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, India
| | - Pradeep Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, India
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28
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He X, Lee B, Jiang Y. Extracellular matrix in cancer progression and therapy. MEDICAL REVIEW (2021) 2022; 2:125-139. [PMID: 37724245 PMCID: PMC10471113 DOI: 10.1515/mr-2021-0028] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 03/31/2022] [Indexed: 09/20/2023]
Abstract
The tumor ecosystem with heterogeneous cellular compositions and the tumor microenvironment has increasingly become the focus of cancer research in recent years. The extracellular matrix (ECM), the major component of the tumor microenvironment, and its interactions with the tumor cells and stromal cells have also enjoyed tremendously increased attention. Like the other components of the tumor microenvironment, the ECM in solid tumors differs significantly from that in normal organs and tissues. We review recent studies of the complex roles the tumor ECM plays in cancer progression, from tumor initiation, growth to angiogenesis and invasion. We highlight that the biomolecular, biophysical, and mechanochemical interactions between the ECM and cells not only regulate the steps of cancer progression, but also affect the efficacy of systemic cancer treatment. We further discuss the strategies to target and modify the tumor ECM to improve cancer therapy.
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Affiliation(s)
- Xiuxiu He
- Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Byoungkoo Lee
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Yi Jiang
- Department of Mathematics and Statistics, Georgia State University, Atlanta, GA, USA
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29
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Proline Dehydrogenase/Proline Oxidase (PRODH/POX) Is Involved in the Mechanism of Metformin-Induced Apoptosis in C32 Melanoma Cell Line. Int J Mol Sci 2022; 23:ijms23042354. [PMID: 35216470 PMCID: PMC8876342 DOI: 10.3390/ijms23042354] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/18/2022] [Accepted: 02/19/2022] [Indexed: 12/15/2022] Open
Abstract
The role of proline dehydrogenase/proline oxidase (PRODH/POX) in the mechanism of antineoplastic activity of metformin (MET) was studied in C32 melanoma cells. PRODH/POX is a mitochondrial enzyme-degrading proline that is implicated in the regulation of cancer cell survival/apoptosis. The enzyme is activated by AMP kinase (AMPK). It has been found that MET induced a significant decrease in cell viability and DNA biosynthesis accompanied by an increase in the expressions of AMPK and PRODH/POX in C32 cells. The mechanism for MET-dependent cytotoxicity on C32 cells was found at the level of PRODH/POX-induced ROS generation and activation of Caspase-3 and Caspase-9 expressions in these cells. The effects were not observed in MET-treated PRODH/POX knock-out C32 cells. Of interest is an MET-dependent increase in the concentration of proline, which is a substrate for PRODH/POX. This phenomenon is due to the MET-dependent inhibition of collagen biosynthesis, which is the main proline-utilizing process. It has been found that the underlying mechanism of anticancer activity of MET involves the activation of AMPK, PRODH/POX, increase in the cytoplasmic concentration of proline, inhibition of collagen biosynthesis, and stimulation of PRODH/POX-dependent ROS generation, which initiate the apoptosis of melanoma cells.
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30
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Gopalan L, Sebastian A, Praul CA, Albert I, Ramachandran R. Metformin Affects the Transcriptomic Profile of Chicken Ovarian Cancer Cells. Genes (Basel) 2021; 13:30. [PMID: 35052372 PMCID: PMC8774788 DOI: 10.3390/genes13010030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/17/2021] [Accepted: 12/20/2021] [Indexed: 11/25/2022] Open
Abstract
Ovarian cancer is the most lethal gynecological malignancy in women. Metformin intake is associated with a reduced incidence of ovarian cancer and increased overall survival rate. We determined the effect of metformin on sphere formation, extracellular matrix invasion, and transcriptome profile of ovarian cancer cells (COVCAR) isolated from ascites of chickens that naturally developed ovarian cancer. We found that metformin treatment significantly decreased sphere formation and invasiveness of COVCAR cells. RNA-Seq data analysis revealed 0, 4, 365 differentially expressed genes in cells treated with 0.5, 1, 2 mM metformin, respectively compared to controls. Transcriptomic and ingenuity pathway analysis (IPA) revealed significant downregulation of MMP7, AICDA, GDPD2, APOC3, APOA1 and predicted inhibition of upstream regulators NFKB, STAT3, TP53 that are involved in epithelial-mesenchymal transition, DNA repair, and lipid metabolism. The analysis revealed significant upregulation of RASD2, IHH, CRABP-1 and predicted activation of upstream regulators VEGF and E2F1 that are associated with angiogenesis and cell cycle. Causal network analysis revealed novel pathways suggesting predicted inhibition of ovarian cancer through master regulator ASCL1 and dataset genes DCX, SEMA6B, HEY2, and KCNIP2. In summary, advanced pathway analysis in IPA revealed novel target genes, upstream regulators, and pathways affected by metformin treatment of COVCAR cells.
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Affiliation(s)
- Lalitha Gopalan
- Department of Animal Science, The Pennsylvania State University, University Park, PA 16802, USA;
| | - Aswathy Sebastian
- The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA; (A.S.); (C.A.P.); (I.A.)
| | - Craig A. Praul
- The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA; (A.S.); (C.A.P.); (I.A.)
| | - Istvan Albert
- The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA; (A.S.); (C.A.P.); (I.A.)
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA
| | - Ramesh Ramachandran
- Department of Animal Science, The Pennsylvania State University, University Park, PA 16802, USA;
- Center for Reproductive Biology and Health, Department of Animal Science, The Pennsylvania State University, University Park, PA 16802, USA
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31
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Ala M, Ala M. Metformin for Cardiovascular Protection, Inflammatory Bowel Disease, Osteoporosis, Periodontitis, Polycystic Ovarian Syndrome, Neurodegeneration, Cancer, Inflammation and Senescence: What Is Next? ACS Pharmacol Transl Sci 2021; 4:1747-1770. [PMID: 34927008 DOI: 10.1021/acsptsci.1c00167] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Indexed: 12/15/2022]
Abstract
Diabetes is accompanied by several complications. Higher prevalence of cancers, cardiovascular diseases, chronic kidney disease (CKD), obesity, osteoporosis, and neurodegenerative diseases has been reported among patients with diabetes. Metformin is the oldest oral antidiabetic drug and can improve coexisting complications of diabetes. Clinical trials and observational studies uncovered that metformin can remarkably prevent or alleviate cardiovascular diseases, obesity, polycystic ovarian syndrome (PCOS), osteoporosis, cancer, periodontitis, neuronal damage and neurodegenerative diseases, inflammation, inflammatory bowel disease (IBD), tuberculosis, and COVID-19. In addition, metformin has been proposed as an antiaging agent. Numerous mechanisms were shown to be involved in the protective effects of metformin. Metformin activates the LKB1/AMPK pathway to interact with several intracellular signaling pathways and molecular mechanisms. The drug modifies the biologic function of NF-κB, PI3K/AKT/mTOR, SIRT1/PGC-1α, NLRP3, ERK, P38 MAPK, Wnt/β-catenin, Nrf2, JNK, and other major molecules in the intracellular signaling network. It also regulates the expression of noncoding RNAs. Thereby, metformin can regulate metabolism, growth, proliferation, inflammation, tumorigenesis, and senescence. Additionally, metformin modulates immune response, autophagy, mitophagy, endoplasmic reticulum (ER) stress, and apoptosis and exerts epigenetic effects. Furthermore, metformin protects against oxidative stress and genomic instability, preserves telomere length, and prevents stem cell exhaustion. In this review, the protective effects of metformin on each disease will be discussed using the results of recent meta-analyses, clinical trials, and observational studies. Thereafter, it will be meticulously explained how metformin reprograms intracellular signaling pathways and alters molecular and cellular interactions to modify the clinical presentations of several diseases.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), 1416753955 Tehran, Iran
| | - Mahan Ala
- School of Dentistry, Golestan University of Medical Sciences (GUMS), 4814565589 Golestan, Iran
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32
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Winter SJ, Miller HA, Steinbach-Rankins JM. Multicellular Ovarian Cancer Model for Evaluation of Nanovector Delivery in Ascites and Metastatic Environments. Pharmaceutics 2021; 13:1891. [PMID: 34834307 PMCID: PMC8625169 DOI: 10.3390/pharmaceutics13111891] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 12/14/2022] Open
Abstract
A novel multicellular model composed of epithelial ovarian cancer and fibroblast cells was developed as an in vitro platform to evaluate nanovector delivery and ultimately aid the development of targeted therapies. We hypothesized that the inclusion of peptide-based scaffold (PuraMatrix) in the spheroid matrix, to represent in vivo tumor microenvironment alterations along with metastatic site conditions, would enhance spheroid cell growth and migration and alter nanovector transport. The model was evaluated by comparing the growth and migration of ovarian cancer cells exposed to stromal cell activation and tissue hypoxia. Fibroblast activation was achieved via the TGF-β1 mediated pathway and tissue hypoxia via 3D spheroids incubated in hypoxia. Surface-modified nanovector transport was assessed via fluorescence and confocal microscopy. Consistent with previous in vivo observations in ascites and at distal metastases, spheroids exposed to activated stromal microenvironment were denser, more contractile and with more migratory cells than nonactivated counterparts. The hypoxic conditions resulted in negative radial spheroid growth over 5 d compared to a radial increase in normoxia. Nanovector penetration attenuated in PuraMatrix regardless of surface modification due to a denser environment. This platform may serve to evaluate nanovector transport based on ovarian ascites and metastatic environments, and longer term, it provide a means to evaluate nanotherapeutic efficacy.
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Affiliation(s)
- Stephen J. Winter
- School of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA;
| | - Hunter A. Miller
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
| | - Jill M. Steinbach-Rankins
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
- Department of Bioengineering, University of Louisville Speed School of Engineering, Louisville, KY 40202, USA
- Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Center for Predictive Medicine, University of Louisville, Louisville, KY 40202, USA
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33
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Wu Z, Zhang C, Najafi M. Targeting of the tumor immune microenvironment by metformin. J Cell Commun Signal 2021; 16:333-348. [PMID: 34611852 DOI: 10.1007/s12079-021-00648-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 09/21/2021] [Indexed: 02/06/2023] Open
Abstract
Stimulating antitumor immunity is an attractive idea for suppressing tumors. CD4 + and CD8 + T cells as well as natural killer cells (NK) are the primary antitumor immune cells in the tumor microenvironment (TME). In contrast to these cells, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs) release several molecules to suppress antitumor immunity and stimulate cancer cell invasion and proliferation. Adjuvant treatment with certain nontoxic agents is interesting to boost antitumor immunity. Metformin, which is known as an antidiabetes drug, can modulate both antitumor and protumor immune cells within TME. It has the ability to induce the proliferation of CD8 + T lymphocytes and NK cells. On the other hand, metformin attenuates polarization toward TAMs, CAFs, and Tregs. Metformin also may stimulate the antitumor activity of immune system cells, while it interrupts the positive cross-talk and interactions between immunosuppressive cells and cancer cells. The purpose of this review is to explain the basic mechanisms for the interactions and communications between immunosuppressive, anti-tumoral, and cancer cells within TME. Next, we discuss the modulating effects of metformin on various cells and secretions in TME.
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Affiliation(s)
- Zihong Wu
- Department of Oncology, The NO.3 People's Hospital of Hubei Province, Jianghan University, Wuhan, 430033, Hubei, China
| | - Caidie Zhang
- Emergency Department, Wuhan Hospital of Traditional Chinese Medicine, Wuhan, 430014, Hubei, China.
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Leng W, Jiang J, Chen B, Wu Q. Metformin and Malignant Tumors: Not Over the Hill. Diabetes Metab Syndr Obes 2021; 14:3673-3689. [PMID: 34429626 PMCID: PMC8380287 DOI: 10.2147/dmso.s326378] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/06/2021] [Indexed: 12/11/2022] Open
Abstract
Malignant tumors are a major cause of death, and their incidence is increasing worldwide. Although the survival rate for some cancers has improved, treatments for other malignant tumors are limited, and their mortality rate continues to increase. People with type 2 diabetes have a higher risk of malignant tumors and a higher mortality rate than those without diabetes. Metformin is a commonly used hypoglycemic drug. In recent years, a growing number of studies have indicated that metformin has antitumor effects and increases the sensitivity of malignant tumors to chemotherapy. However, the effect of metformin on different tumors is currently controversial, and the mechanism of metformin's antitumor action is not fully understood. Insights into the effect of metformin on malignant tumors and the possible mechanism may contribute to the development of antitumor drugs.
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Affiliation(s)
- Weiling Leng
- Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Juan Jiang
- Endocrinology and Nephrology Department, Chongqing University Cancer Hospital and Chongqing Cancer Institute and Chongqing Cancer Hospital, Chongqing, People’s Republic of China
| | - Bing Chen
- Endocrinology Department, The First Affiliated Hospital of the Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China
| | - Qinan Wu
- Endocrinology Department, Dazu Hospital of Chongqing Medical University, The People’s Hospital of Dazu, Chongqing, People’s Republic of China
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Singh SK, Apata T, Singh S, McFadden M, Singh R. Clinical Implication of Metformin in Relation to Diabetes Mellitus and Ovarian Cancer. Biomedicines 2021; 9:biomedicines9081020. [PMID: 34440224 PMCID: PMC8394937 DOI: 10.3390/biomedicines9081020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/11/2021] [Accepted: 08/13/2021] [Indexed: 11/16/2022] Open
Abstract
Since multiple reports established an association between diabetes mellitus and various cancers, emerging studies have surfaced to understand the effects of metformin as an anti-cancer agent. Although there was previous, but conflicting evidence, of a relationship between diabetes and ovarian cancer (OvCa), recent studies have supported this association. The mechanism of cancer development in patients with diabetes is likely to involve hyperglycemia, hyperinsulinemia, chronic inflammation, reactive oxygen species, regulation of cellular homeostasis, and activation of various pathways that lead to tumor cell proliferation. Preclinical evidence indicating that metformin, a medication commonly used to treat type 2 diabetes mellitus, may protect against OvCa. Metformin exerts anti-cancer properties by activating the MAPK pathway, inhibiting the PI3K/AKT/mTOR pathway, increasing tumor suppressor genes, inducing G2/M cycle arrest, and various other processes. Several studies have shown the efficacy of metformin as an adjunct with standard chemotherapeutic agents due to its synergistic effects on OvCa cells. This review highlights the epidemiologic evidence supporting a link between diabetes and OvCa, the fundamental molecular mechanism underlying carcinogenesis in patients with diabetes, the anti-cancer effects of metformin, and the need for further clinical investigations on combination therapies with metformin and standard chemotherapeutic agents for OvCa.
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Affiliation(s)
- Santosh Kumar Singh
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA; (S.K.S.); (T.A.); (M.M.)
| | - Tejumola Apata
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA; (S.K.S.); (T.A.); (M.M.)
| | - Shriti Singh
- Department of Kriya Sharir, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India;
| | - Melayshia McFadden
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA; (S.K.S.); (T.A.); (M.M.)
| | - Rajesh Singh
- Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA; (S.K.S.); (T.A.); (M.M.)
- Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA
- Correspondence: ; Tel.: +1-404-756-6661; Fax: +1-404-752-1179
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Eckert MA, Orozco C, Xiao J, Javellana M, Lengyel E. The Effects of Chemotherapeutics on the Ovarian Cancer Microenvironment. Cancers (Basel) 2021; 13:3136. [PMID: 34201616 PMCID: PMC8268261 DOI: 10.3390/cancers13133136] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/06/2021] [Accepted: 06/07/2021] [Indexed: 12/31/2022] Open
Abstract
High-grade serous ovarian cancer (HGSOC) is characterized by a complex and dynamic tumor microenvironment (TME) composed of cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and adipocytes. Although most approved therapies target cancer cells, a growing body of evidence suggests that chemotherapeutic agents have an important role in regulating the biology of the diverse cells that compose the TME. Understanding how non-transformed cells respond and adapt to established therapeutics is necessary to completely comprehend their action and develop novel therapeutics that interrupt undesired tumor-stroma interactions. Here, we review the effects of chemotherapeutic agents on normal cellular components of the host-derived TME focusing on CAFs. We concentrate on therapies used in the treatment of HGSOC and synthesize findings from studies focusing on other cancer types and benign tissues. Agents such as platinum derivatives, taxanes, and PARP inhibitors broadly affect the TME and promote or inhibit the pro-tumorigenic roles of CAFs by modifying the bidirectional cross-talk between tumor and stromal cells in the tumor organ. While most chemotherapy research focuses on cancer cells, these studies emphasize the need to consider all cell types within the tumor organ when evaluating chemotherapeutics.
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Affiliation(s)
| | | | | | | | - Ernst Lengyel
- Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA; (M.A.E.); (C.O.); (J.X.); (M.J.)
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PARP inhibitors promote stromal fibroblast activation by enhancing CCL5 autocrine signaling in ovarian cancer. NPJ Precis Oncol 2021; 5:49. [PMID: 34108603 PMCID: PMC8190269 DOI: 10.1038/s41698-021-00189-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 05/13/2021] [Indexed: 11/21/2022] Open
Abstract
Cancer-associated fibroblasts (CAFs) play significant roles in drug resistance through different ways. Antitumor therapies, including molecular targeted interventions, not only effect tumor cells but also modulate the phenotype and characteristics of CAFs, which can in turn blunt the therapeutic response. Little is known about how stromal fibroblasts respond to poly (ADP-ribose) polymerase inhibitors (PARPis) in ovarian cancer (OC) and subsequent effects on tumor cells. This is a study to evaluate how CAFs react to PARPis and their potential influence on PARPi resistance in OC. We discovered that OC stromal fibroblasts exhibited intrinsic resistance to PARPis and were further activated after the administration of PARPis. PARPi-challenged fibroblasts displayed a specific secretory profile characterized by increased secretion of CCL5, MIP-3α, MCP3, CCL11, and ENA-78. Mechanistically, increased secretion of CCL5 through activation of the NF-κB signaling pathway was required for PARPi-induced stromal fibroblast activation in an autocrine manner. Moreover, neutralizing CCL5 partly reversed PARPi-induced fibroblast activation and boosted the tumor inhibitory effect of PARPis in both BRCA1/2-mutant and BRCA1/2-wild type xenograft models. Our study revealed that PARPis could maintain and improve stromal fibroblast activation involving CCL5 autocrine upregulation. Targeting CCL5 might offer a new treatment modality in overcoming the reality of PARPi resistance in OC.
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Komen J, van Neerven SM, van den Berg A, Vermeulen L, van der Meer AD. Mimicking and surpassing the xenograft model with cancer-on-chip technology. EBioMedicine 2021; 66:103303. [PMID: 33773183 PMCID: PMC8024912 DOI: 10.1016/j.ebiom.2021.103303] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 03/04/2021] [Accepted: 03/10/2021] [Indexed: 01/11/2023] Open
Abstract
Organs-on-chips are in vitro models in which human tissues are cultured in microfluidic compartments with a controlled, dynamic micro-environment. Specific organs-on-chips are being developed to mimic human tumors, but the validation of such 'cancer-on-chip' models for use in drug development is hampered by the complexity and variability of human tumors. An important step towards validation of cancer-on-chip technology could be to first mimic cancer xenograft models, which share multiple characteristics with human cancers but are significantly less complex. Here we review the relevant biological characteristics of a xenograft tumor and show that organ-on-chip technology is capable of mimicking many of these aspects. Actual comparisons between on-chip tumor growth and xenografts are promising but also demonstrate that further development and empirical validation is still needed. Validation of cancer-on-chip models to xenografts would not only represent an important milestone towards acceptance of cancer-on-chip technology, but could also improve drug discovery, personalized cancer medicine, and reduce animal testing.
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Affiliation(s)
- Job Komen
- BIOS Lab on a Chip group, MESA+ Institute for Nanotechnology, University of Twente, P. O. Box 217, 7500 AE Enschede, the Netherlands.
| | - Sanne M van Neerven
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, 1105 AZ, Amsterdam, the Netherlands
| | - Albert van den Berg
- BIOS Lab on a Chip group, MESA+ Institute for Nanotechnology, University of Twente, P. O. Box 217, 7500 AE Enschede, the Netherlands
| | - Louis Vermeulen
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centers, 1105 AZ, Amsterdam, the Netherlands
| | - Andries D van der Meer
- Applied Stem Cell Technologies, TechMed Centre, University of Twente, P. O. Box 217, 7500 AE Enschede, the Netherlands
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Kathuria D, Raul AD, Wanjari P, Bharatam PV. Biguanides: Species with versatile therapeutic applications. Eur J Med Chem 2021; 219:113378. [PMID: 33857729 DOI: 10.1016/j.ejmech.2021.113378] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 03/04/2021] [Accepted: 03/08/2021] [Indexed: 12/18/2022]
Abstract
Biguanides are compounds in which two guanidine moieties are fused to form a highly conjugated system. Biguanides are highly basic and hence they are available as salts mostly hydrochloride salts, these cationic species have been found to exhibit many therapeutic properties. This review covers the research and development carried out on biguanides and accounts the various therapeutic applications of drugs containing biguanide group-such as antimalarial, antidiabetic, antiviral, anticancer, antibacterial, antifungal, anti-tubercular, antifilarial, anti-HIV, as well as other biological activities. The aim of this review is to compile all the medicinal chemistry applications of this class of compounds so as to pave way for the accelerated efforts in finding the drug action mechanisms associated with this class of compounds. Importance has been given to the organic chemistry of these biguanide derivatives also.
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Affiliation(s)
- Deepika Kathuria
- University Center for Research and Development, Chandigarh University, Gharuan, Punjab, 140413, India
| | - Akshay D Raul
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India
| | - Pravin Wanjari
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India
| | - Prasad V Bharatam
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar, 160 062, Punjab, India.
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Bishnu A, Phadte P, Dhadve A, Sakpal A, Rekhi B, Ray P. Molecular imaging of the kinetics of hyperactivated ERK1/2-mediated autophagy during acquirement of chemoresistance. Cell Death Dis 2021; 12:161. [PMID: 33558461 PMCID: PMC7870816 DOI: 10.1038/s41419-021-03451-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 01/19/2021] [Accepted: 01/19/2021] [Indexed: 12/16/2022]
Abstract
Alterations in key kinases and signaling pathways can fine-tune autophagic flux to promote the development of chemoresistance. Despite empirical evidences of strong association between enhanced autophagic flux with acquired chemoresistance, it is still not understood whether an ongoing autophagic flux is required for both initiation, as well as maintenance of chemoresistance, or is sufficient for one of the either steps. Utilizing indigenously developed cisplatin-paclitaxel-resistant models of ovarian cancer cells, we report an intriguing oscillation in chemotherapy-induced autophagic flux across stages of resistance, which was found to be specifically elevated at the early stages or onset of chemoresistance. Conversely, the sensitive cells and cells at late stages of resistance showed stalled and reduced autophagic flux. This increased flux at early stages of resistance was found to be dictated by a hyperactive ERK1/2 signaling, which when inhibited either pharmacologically (U0126/Trametinib) or genetically, reduced p62 degradation, number of LC3+veLAMP1+ve puncta, autophagolysosome formation, and led to chemo-sensitization and apoptosis. Inhibition of ERK1/2 activation also altered the level of UVRAG and Rab7, the two key proteins involved in autophagosome-lysosome fusion. Noninvasive imaging of autophagic flux using a novel autophagy sensor (mtFL-p62 fusion reporter) showed that combinatorial treatment of platinum-taxol along with Trametinib/chloroquine blocked autophagic flux in live cells and tumor xenografts. Interestingly, Trametinib was found to be equally effective in blocking autophagic flux as chloroquine both in live cells and tumor xenografts. Combinatorial treatment of Trametinib and platinum-taxol significantly reduced tumor growth. This is probably the first report of real-time monitoring of chemotherapy-induced autophagy kinetics through noninvasive bioluminescence imaging in preclinical mouse model. Altogether our data suggest that an activated ERK1/2 supports proper completion of autophagic flux at the onset of chemoresistance to endure initial chemotherapeutic insult and foster the development of a highly chemoresistant phenotype, where autophagy becomes dispensable.
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Affiliation(s)
- Aniketh Bishnu
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, TMC, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Pratham Phadte
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, TMC, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Ajit Dhadve
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, TMC, Navi Mumbai, 410210, India
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India
| | - Asmita Sakpal
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, TMC, Navi Mumbai, 410210, India
| | - Bharat Rekhi
- Department of Pathology, Tata Memorial Hospital, Mumbai, 400012, India
| | - Pritha Ray
- Imaging Cell Signalling & Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer, TMC, Navi Mumbai, 410210, India.
- Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400094, India.
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Pitman M, Oehler MK, Pitson SM. Sphingolipids as multifaceted mediators in ovarian cancer. Cell Signal 2021; 81:109949. [PMID: 33571664 DOI: 10.1016/j.cellsig.2021.109949] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 02/04/2021] [Accepted: 02/05/2021] [Indexed: 12/19/2022]
Abstract
Ovarian cancer is the most lethal gynaecological malignancy. It is commonly diagnosed at advanced stage when it has metastasised to the abdominal cavity and treatment becomes very challenging. While current standard therapy involving debulking surgery and platinum + taxane-based chemotherapy is associated with high response rates initially, the large majority of patients relapse and ultimately succumb to chemotherapy-resistant disease. In order to improve survival novel strategies for early detection and therapeutics against treatment-refractory disease are urgently needed. A promising new target against ovarian cancer is the sphingolipid pathway which is commonly hijacked in cancer to support cell proliferation and survival and has been shown to promote chemoresistance and metastasis in a wide range of malignant neoplasms. In particular, the sphingosine kinase 1-sphingosine 1-phosphate receptor 1 axis has been shown to be altered in ovarian cancer in multiple ways and therefore represents an attractive therapeutic target. Here we review the roles of sphingolipids in ovarian cancer progression, metastasis and chemoresistance, highlighting novel strategies to target this pathway that represent potential avenues to improve patient survival.
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Affiliation(s)
- MelissaR Pitman
- Centre for Cancer Biology, University of South Australia and SA Pathology, UniSA CRI Building, North Tce, Adelaide, SA 5000, Australia.
| | - Martin K Oehler
- Adelaide Medical School, University of Adelaide, Adelaide, SA 5000, Australia; School of Paediatrics and Reproductive Health, Robinson Research Institute, University of Adelaide, South Australia, Australia; Department of Gynaecological Oncology, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Stuart M Pitson
- Centre for Cancer Biology, University of South Australia and SA Pathology, UniSA CRI Building, North Tce, Adelaide, SA 5000, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA 5000, Australia; School of Biological Sciences, University of Adelaide, Adelaide, Australia.
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Bai B, Chen H. Metformin: A Novel Weapon Against Inflammation. Front Pharmacol 2021; 12:622262. [PMID: 33584319 PMCID: PMC7880161 DOI: 10.3389/fphar.2021.622262] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/04/2021] [Indexed: 12/11/2022] Open
Abstract
It has become widely accepted that inflammation is a driving force behind a variety of chronic diseases, such as cardiovascular disease, diabetes, kidney disease, cancer, neurodegenerative disorders, etc. However, the existing nonsteroidal anti-inflammatory drugs show a limited utility in clinical patients. Therefore, the novel agents with different inflammation-inhibitory mechanisms are worth pursuing. Metformin, a synthetic derivative of guanidine, has a history of more than 50 years of clinical experience in treating patients with type 2 diabetes. Intense research efforts have been dedicated to proving metformin’s inflammation-inhibitory effects in cells, animal models, patient records, and randomized clinical trials. The emerging evidence also indicates its therapeutic potential in clinical domains other than type 2 diabetes. Herein, this article appraises current pre-clinical and clinical findings, emphasizing metformin’s anti-inflammatory properties under individual pathophysiological scenarios. In summary, the anti-inflammatory effects of metformin are evident in pre-clinical models. By comparison, there are still clinical perplexities to be addressed in repurposing metformin to inflammation-driven chronic diseases. Future randomized controlled trials, incorporating better stratification/targeting, would establish metformin’s utility in this clinical setting.
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Affiliation(s)
- Bo Bai
- Department of Cardiology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Haibo Chen
- Department of Cardiology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
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Tsogas FK, Majerczyk D, Hart PC. Possible Role of Metformin as an Immune Modulator in the Tumor Microenvironment of Ovarian Cancer. Int J Mol Sci 2021; 22:ijms22020867. [PMID: 33467127 PMCID: PMC7830067 DOI: 10.3390/ijms22020867] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 01/13/2021] [Indexed: 12/14/2022] Open
Abstract
Growing evidence suggests that the immune component of the tumor microenvironment (TME) may be highly involved in the progression of high-grade serous ovarian cancer (HGSOC), as an immunosuppressive TME is associated with worse patient outcomes. Due to the poor prognosis of HGSOC, new therapeutic strategies targeting the TME may provide a potential path forward for preventing disease progression to improve patient survival. One such postulated approach is the repurposing of the type 2 diabetes medication, metformin, which has shown promise in reducing HGSOC tumor progression in retrospective epidemiological analyses and through numerous preclinical studies. Despite its potential utility in treating HGSOC, and that the immune TME is considered as a key factor in the disease’s progression, little data has definitively shown the ability of metformin to target this component of the TME. In this brief review, we provide a summary of the current understanding of the effects of metformin on leukocyte function in ovarian cancer and, coupled with data from other related disease states, posit the potential mechanisms by which the drug may enhance the anti-tumorigenic effects of immune cells to improve HGSOC patient survival.
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Affiliation(s)
- Faye K. Tsogas
- College of Science, Health and Pharmacy, Roosevelt University, Schaumburg, IL 60173, USA; (F.K.T.); (D.M.)
| | - Daniel Majerczyk
- College of Science, Health and Pharmacy, Roosevelt University, Schaumburg, IL 60173, USA; (F.K.T.); (D.M.)
- Loyola Medicine, Berwyn, IL 60402, USA
| | - Peter C. Hart
- College of Science, Health and Pharmacy, Roosevelt University, Schaumburg, IL 60173, USA; (F.K.T.); (D.M.)
- Correspondence:
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Biffi G, Tuveson DA. Diversity and Biology of Cancer-Associated Fibroblasts. Physiol Rev 2021; 101:147-176. [PMID: 32466724 PMCID: PMC7864232 DOI: 10.1152/physrev.00048.2019] [Citation(s) in RCA: 733] [Impact Index Per Article: 183.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 05/19/2020] [Accepted: 05/20/2020] [Indexed: 02/08/2023] Open
Abstract
Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the progression of the tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands, and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance, and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity, and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing preclinical and clinical evaluation.
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Affiliation(s)
- Giulia Biffi
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York; and Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
| | - David A Tuveson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York; and Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
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Tang Z, Tang N, Jiang S, Bai Y, Guan C, Zhang W, Fan S, Huang Y, Lin H, Ying Y. The Chemosensitizing Role of Metformin in Anti-Cancer Therapy. Anticancer Agents Med Chem 2021; 21:949-962. [PMID: 32951587 DOI: 10.2174/1871520620666200918102642] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/23/2020] [Accepted: 08/08/2020] [Indexed: 11/22/2022]
Abstract
Chemoresistance, which leads to the failure of chemotherapy and further tumor recurrence, presents the largest hurdle for the success of anti-cancer therapy. In recent years, metformin, a widely used first-line antidiabetic drug, has attracted increasing attention for its anti-cancer effects. A growing body of evidence indicates that metformin can sensitize tumor responses to different chemotherapeutic drugs, such as hormone modulating drugs, anti-metabolite drugs, antibiotics, and DNA-damaging drugs via selective targeting of Cancer Stem Cells (CSCs), improving the hypoxic microenvironment, and by suppressing tumor metastasis and inflammation. In addition, metformin may regulate metabolic programming, induce apoptosis, reverse Epithelial to Mesenchymal Transition (EMT), and Multidrug Resistance (MDR). In this review, we summarize the chemosensitization effects of metformin and focus primarily on its molecular mechanisms in enhancing the sensitivity of multiple chemotherapeutic drugs, through targeting of mTOR, ERK/P70S6K, NF-κB/HIF-1 α, and Mitogen- Activated Protein Kinase (MAPK) signaling pathways, as well as by down-regulating the expression of CSC genes and Pyruvate Kinase isoenzyme M2 (PKM2). Through a comprehensive understanding of the molecular mechanisms of chemosensitization provided in this review, the rationale for the use of metformin in clinical combination medications can be more systematically and thoroughly explored for wider adoption against numerous cancer types.>.
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Affiliation(s)
- Zhimin Tang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Nan Tang
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330006, China
| | - Shanshan Jiang
- Institute of Hematological Research, Shanxi Provincial People's Hospital, Xian 710000, China
| | - Yangjinming Bai
- Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang 330006, China
| | - Chenxi Guan
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Wansi Zhang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Shipan Fan
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou 510005, China
| | - Yonghong Huang
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Hui Lin
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
| | - Ying Ying
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
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Abstract
The immune system plays an essential and central role in tumor cell differentiation, proliferation, angiogenesis, apoptosis, invasion, and metastasis. Over the past decade, cancer therapy has rapidly evolved from traditional approaches, such as surgery, chemotherapy, and radiotherapy, to revolutionary new treatment options with immunotherapy. This new era of cancer treatment options has now been clinically tested and applied to many forms of human malignancies, often with quite dramatic results. As we develop more effective combinations of cancer treatment, several agents have been recently investigated, putatively identified as anticancer agents, or immunostimulatory molecules. One such agent is metformin, originally developed as a fairly standard first-line therapy for patients with type-2 diabetes mellitus (T2DM). Given the underlying mechanisms of action, researchers began to examine the alternative functions and possible utility of metformin, finding that the cancer risk in patients with T2DM was reduced. It appears that metformin, at least in part, has an antitumor effect through activation of the 5' adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Moreover, numerous studies have demonstrated that metformin interferes with key immunopathological mechanisms that are involved in the pathological processes or associated with malignant progression. Such insights may shed light on further analyzing whether metformin enhances the effectiveness of the immunotherapy and overcomes the immunotherapy resistance in the patients. Herein, we provide a comprehensive review of the literature examining the impact of metformin upon the host immune system and cancer immunity.
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Affiliation(s)
- Ruixia Ma
- Department of Genetics, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, 221000, China
| | - Bin Yi
- Department of Genetics, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Adam I Riker
- Geaton and JoAnn DeCesaris Cancer Institute, Anne Arundel Medical Center, Luminis Health, Annapolis, MD, USA.
| | - Yaguang Xi
- Department of Genetics, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
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47
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Mitochondria at Center of Exchanges between Cancer Cells and Cancer-Associated Fibroblasts during Tumor Progression. Cancers (Basel) 2020; 12:cancers12103017. [PMID: 33080792 PMCID: PMC7603005 DOI: 10.3390/cancers12103017] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/14/2020] [Accepted: 10/14/2020] [Indexed: 01/10/2023] Open
Abstract
Simple Summary Malignant cells and their supportive associated fibroblasts (CAFs) exchange various molecules that promote energy production, biosynthesis and therapy resistance by modulating mitochondrial activity and dynamics. We herein review molecular exchanges from CAFs to malignant cells that support tumor growth and therapy resistance, and we highlight the crucial role of CAFs mitochondria in this support. This implies (1) reciprocal mitochondrial control by malignant cells and (2) fibroblast activation. Finally, we discuss therapeutic strategies that could improve current therapies by targeting mitochondrial-mediated dialogue between the two cell types. Abstract Resistance of solid cancer cells to chemotherapies and targeted therapies is not only due to the mutational status of cancer cells but also to the concurring of stromal cells of the tumor ecosystem, such as immune cells, vasculature and cancer-associated fibroblasts (CAFs). The reciprocal education of cancer cells and CAFs favors tumor growth, survival and invasion. Mitochondrial function control, including the regulation of mitochondrial metabolism, oxidative stress and apoptotic stress are crucial for these different tumor progression steps. In this review, we focus on how CAFs participate in cancer progression by modulating cancer cells metabolic functions and mitochondrial apoptosis. We emphasize that mitochondria from CAFs influence their activation status and pro-tumoral effects. We thus advocate that understanding mitochondria-mediated tumor–stroma interactions provides the possibility to consider cancer therapies that improve current treatments by targeting these interactions or mitochondria directly in tumor and/or stromal cells.
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48
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Li Z, Li X, He X, Jia X, Zhang X, Lu B, Zhao J, Lu J, Chen L, Dong Z, Liu K, Dong Z. Proteomics Reveal the Inhibitory Mechanism of Levodopa Against Esophageal Squamous Cell Carcinoma. Front Pharmacol 2020; 11:568459. [PMID: 33101026 PMCID: PMC7546765 DOI: 10.3389/fphar.2020.568459] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 09/04/2020] [Indexed: 12/22/2022] Open
Abstract
High recurrence rates and poor survival of patients with esophageal squamous cell carcinoma (ESCC) after treatment make ongoing research on chemoprevention drugs for ESCC particularly important. In this study, we screened a large number of FDA-approved drugs and found levodopa, a drug used to treat Parkinson's disease, had an inhibitory effect on the growth of ESCC cells. To elucidate the molecular mechanisms involved, we applied quantitative proteomics to investigate the anti-tumor activity of levodopa on ESCC. The results suggest that levodopa could down-regulate oxidative phosphorylation, non-alcoholic fatty liver disease, and Parkinson's disease pathways. Major mitochondrial respiratory compounds were involved in the pathways, including succinate dehydrogenase subunit D, NADH-ubiquinone oxidoreductase Fe-S protein 4, and mitochondrial cytochrome c oxidase subunit 3. Down-regulation of these proteins was associated with mitochondrial dysfunction. Western blotting and immunofluorescence results confirmed the proteomics findings. Cell viability assays indicated mitochondrial activity was suppressed after levodopa treatment. Reduced mitochondrial membrane potential was detected using JC-1 staining and TMRE assays. Transmission electron microscopy revealed changes in the morphology of mitochondria. Taken together, these results indicate that levodopa inhibited the growth of ESCC through restraining mitochondria function.
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Affiliation(s)
- Zhenzhen Li
- Department of Pathophysiology, School of Basic Medical Sciences, AMS, College of Medicine, Zhengzhou University, Zhengzhou, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Xin Li
- Department of Pathophysiology, School of Basic Medical Sciences, AMS, College of Medicine, Zhengzhou University, Zhengzhou, China
| | - Xinyu He
- Department of Pathophysiology, School of Basic Medical Sciences, AMS, College of Medicine, Zhengzhou University, Zhengzhou, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Xuechao Jia
- Department of Pathophysiology, School of Basic Medical Sciences, AMS, College of Medicine, Zhengzhou University, Zhengzhou, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Xiaofan Zhang
- Department of Pathophysiology, School of Basic Medical Sciences, AMS, College of Medicine, Zhengzhou University, Zhengzhou, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Bingbing Lu
- Department of Pathophysiology, School of Basic Medical Sciences, AMS, College of Medicine, Zhengzhou University, Zhengzhou, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Jimin Zhao
- Department of Pathophysiology, School of Basic Medical Sciences, AMS, College of Medicine, Zhengzhou University, Zhengzhou, China.,Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, China
| | - Jing Lu
- Department of Pathophysiology, School of Basic Medical Sciences, AMS, College of Medicine, Zhengzhou University, Zhengzhou, China.,Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, China
| | - Lexia Chen
- Department of Pathophysiology, School of Basic Medical Sciences, AMS, College of Medicine, Zhengzhou University, Zhengzhou, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, China
| | - Ziming Dong
- Department of Pathophysiology, School of Basic Medical Sciences, AMS, College of Medicine, Zhengzhou University, Zhengzhou, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.,Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, China
| | - Kangdong Liu
- Department of Pathophysiology, School of Basic Medical Sciences, AMS, College of Medicine, Zhengzhou University, Zhengzhou, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.,Henan Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, China.,Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, China
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, AMS, College of Medicine, Zhengzhou University, Zhengzhou, China.,China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, China.,Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, China
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49
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PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis 2020; 11:797. [PMID: 32973135 PMCID: PMC7515865 DOI: 10.1038/s41419-020-02998-6] [Citation(s) in RCA: 521] [Impact Index Per Article: 104.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 08/17/2020] [Accepted: 08/27/2020] [Indexed: 12/13/2022]
Abstract
Multidrug resistance (MDR) is the dominant challenge in the failure of chemotherapy in cancers. Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that spreads intracellular signal cascades and regulates a variety of cellular processes. PI3Ks are considered significant causes of chemoresistance in cancer therapy. Protein kinase B (AKT) is also a significant downstream effecter of PI3K signaling, and it modulates several pathways, including inhibition of apoptosis, stimulation of cell growth, and modulation of cellular metabolism. This review highlights the aberrant activation of PI3K/AKT as a key link that modulates MDR. We summarize the regulation of numerous major targets correlated with the PI3K/AKT pathway, which is further related to MDR, including the expression of apoptosis-related protein, ABC transport and glycogen synthase kinase-3 beta (GSK-3β), synergism with nuclear factor kappa beta (NF-κB) and mammalian target of rapamycin (mTOR), and the regulation of glycolysis.
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50
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Hart PC, Kenny HA, Grassl N, Watters KM, Litchfield LM, Coscia F, Blaženović I, Ploetzky L, Fiehn O, Mann M, Lengyel E, Romero IL. Mesothelial Cell HIF1α Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk. Cell Rep 2020; 29:4086-4098.e6. [PMID: 31851935 DOI: 10.1016/j.celrep.2019.11.079] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 10/04/2019] [Accepted: 11/19/2019] [Indexed: 01/04/2023] Open
Abstract
The tumor microenvironment (TME) plays a pivotal role in cancer progression, and, in ovarian cancer (OvCa), the primary TME is the omentum. Here, we show that the diabetes drug metformin alters mesothelial cells in the omental microenvironment. Metformin interrupts bidirectional signaling between tumor and mesothelial cells by blocking OvCa cell TGF-β signaling and mesothelial cell production of CCL2 and IL-8. Inhibition of tumor-stromal crosstalk by metformin is caused by the reduced expression of the tricarboxylic acid (TCA) enzyme succinyl CoA ligase (SUCLG2). Through repressing this TCA enzyme and its metabolite, succinate, metformin activated prolyl hydroxylases (PHDs), resulting in the degradation of hypoxia-inducible factor 1α (HIF1α) in mesothelial cells. Disruption of HIF1α-driven IL-8 signaling in mesothelial cells by metformin results in reduced OvCa invasion in an organotypic 3D model. These findings indicate that tumor-promoting signaling between mesothelial and OvCa cells in the TME can be targeted using metformin.
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Affiliation(s)
- Peter C Hart
- Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA
| | - Hilary A Kenny
- Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA
| | - Niklas Grassl
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, Germany
| | - Karen M Watters
- Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA
| | - Lacey M Litchfield
- Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA
| | - Fabian Coscia
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, Germany
| | - Ivana Blaženović
- West Coast Metabolomics Center, University of California, Davis Genome Center, Davis, CA, USA
| | - Lisa Ploetzky
- West Coast Metabolomics Center, University of California, Davis Genome Center, Davis, CA, USA
| | - Oliver Fiehn
- West Coast Metabolomics Center, University of California, Davis Genome Center, Davis, CA, USA
| | - Matthias Mann
- Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried 82152, Germany
| | - Ernst Lengyel
- Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA.
| | - Iris L Romero
- Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL 60637, USA.
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