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Wu N, Han Z, Lv W, Huang Y, Zhu J, Deng J, Xue Q. Reprogramming peritoneal macrophages with outer membrane vesicle-coated PLGA nanoparticles for endometriosis prevention. Biomaterials 2025; 319:123198. [PMID: 40015004 DOI: 10.1016/j.biomaterials.2025.123198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 01/23/2025] [Accepted: 02/16/2025] [Indexed: 03/01/2025]
Abstract
Endometriosis is a chronic inflammatory disease that primarily affects women of reproductive age. The current hormonal treatments are unsuitable for women who wish to conceive, highlighting the need for non-hormonal therapeutic alternatives. In this study, we engineered outer membrane vesicle (OMV)-coated poly (lactic-co-glycolic acid) (PLGA) nanoparticles (OMV-NPs) as a potential therapy for endometriosis. These OMV-NPs were internalized by macrophages more efficiently than bacterial OMVs and preserved the immunostimulatory properties of OMVs. In vivo administration of OMV-NPs in mice achieved prolonged retention in the peritoneal cavity, with effective uptake by nearly 80 % of the peritoneal macrophages. Notably, treatment with OMV-NPs reprogrammed macrophages toward the M1 phenotype, resulting in a significant decrease in the M2 to M1 ratio within the peritoneal cavity and in endometriotic lesions. This shift from M2 to M1 was associated with reduced TGF-β1 production and suppressed myofibroblast activation, which led to substantial inhibition of endometriosis progression. Furthermore, immunohistochemical imaging of paired eutopic and ectopic endometrial tissues from endometriosis patients revealed a positive correlation between M2-polarized macrophages and fibrosis. This finding suggests that reprogramming macrophages with OMV-NPs could be a promising therapeutic approach for endometriosis.
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Affiliation(s)
- Ning Wu
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China
| | - Ziwei Han
- Beijing Engineering Research Center for BioNanotechnology, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, National Center for Nanoscience and Technology, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wenxing Lv
- Beijing Engineering Research Center for BioNanotechnology, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, National Center for Nanoscience and Technology, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yanjuan Huang
- Beijing Engineering Research Center for BioNanotechnology, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, National Center for Nanoscience and Technology, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jingwen Zhu
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China
| | - Jinqi Deng
- Beijing Engineering Research Center for BioNanotechnology, CAS Key Laboratory of Standardization and Measurement for Nanotechnology, National Center for Nanoscience and Technology, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Qing Xue
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China.
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Deipenbrock A, Wilmes BE, Sommermann T, Abdo N, Moustakas K, Raasch M, Rennert K, Teusch NE. Modelling of the multicellular tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) on a fit-for-purpose biochip for preclinical drug discovery. LAB ON A CHIP 2025; 25:2168-2181. [PMID: 40018951 DOI: 10.1039/d4lc01016g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer. One major cause for a fast disease progression is the presence of a highly fibrotic tumor microenvironment (TME) mainly composed of cancer-associated fibroblasts (CAF), and various immune cells, especially tumor-associated macrophages (TAM). To conclusively evaluate drug efficacy, it is crucial to develop in vitro models that can recapitulate the cross talk between tumor cells and the surrounding stroma. Here, we constructed a fit-for-purpose biochip platform which allows the integration of PDAC spheroids (composed of PANC-1 cells and pancreatic stellate cells (PSC)). Additionally, the chip design enables dynamic administration of drugs or immune cells via a layer of human umbilical vein endothelial cells (HUVEC). As a proof-of-concept for drug administration, vorinostat, an FDA-approved histone deacetylase inhibitor for cutaneous T cell lymphoma (CTCL), subjected via continuous flow for 72 h, resulted in a significantly reduced viability of PDAC spheroids without affecting vascular integrity. Furthermore, dynamic perfusion with peripheral mononuclear blood cells (PBMC)-derived monocytes resulted in an immune cell migration through the endothelium into the spheroids. After 72 h of infiltration, monocytes differentiated into macrophages which polarized into the M2 phenotype. The polarization into M2 macrophages persisted for at least 168 h, verified by expression of the M2 marker CD163 which increased from 72 h to 168 h, while the M1 markers CD86 and HLA-DR were significantly downregulated. Overall, the described spheroid-on-chip model allows the evaluation of novel therapeutic strategies by mimicking and targeting the complex TME of PDAC.
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Affiliation(s)
- Alina Deipenbrock
- Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
| | - Ben Eric Wilmes
- Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
| | | | | | - Kyra Moustakas
- Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
| | | | | | - Nicole E Teusch
- Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
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Wang X, Bao H, Wang Y, Wang Y, Guo C, Wu Y, Xu Y, Li Y. Innovative peptide therapeutics targeting IL17RA to regulate inflammatory responses. Sci Rep 2025; 15:8542. [PMID: 40121226 PMCID: PMC11929782 DOI: 10.1038/s41598-025-92915-8] [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: 12/12/2024] [Accepted: 03/03/2025] [Indexed: 03/25/2025] Open
Abstract
Interleukin-17 receptor A (IL17RA) is a critical mediator of pro-inflammatory cytokine signaling and a key immune checkpoint in autoimmune diseases. While monoclonal antibodies targeting IL17RA have demonstrated clinical efficacy, their high costs, complexity in production, and lack of oral bioavailability present significant limitations. In response to these challenges, we developed AL-8(0), a novel peptide specifically designed to inhibit the IL17A-IL17RA signaling pathway. AL-8(0) was synthesized with high purity and systematically evaluated for its binding affinity and anti-inflammatory activity. Biophysical and cellular assays confirmed the peptide's strong affinity for IL17RA and its ability to inhibit inflammatory cytokine production in IL17RA-expressing monocyte-macrophages and keratinocytes. Moreover, its anti-inflammatory effects were com-parable to IL17RA-targeting monoclonal antibodies and were dependent on IL17RA expression, as demonstrated by experiments using IL17RA-deficient cells. These results underscore AL-8(0)'s potential as a targeted therapeutic for autoimmune diseases, offering a peptide-based alternative with lower antigenicity, improved scalability, and potential for oral administration. This study lays the groundwork for further development of AL-8(0) and similar peptides as innovative treatments for inflammatory disorders driven by the IL17A-IL17RA pathway.
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Affiliation(s)
- Xinmin Wang
- School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, 014010, China
| | - Hang Bao
- School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, 014010, China
| | - Yuya Wang
- Inner Mongolia Autonomous Region People's Hospital, Hohhot, 010010, China
| | - Yalu Wang
- The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, 014010, China
| | - Cheng Guo
- School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, 014010, China
| | - Yanning Wu
- School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, 014010, China
| | - Yongbin Xu
- School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, 014010, China
| | - Yali Li
- School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, 014010, China.
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Xiang J, Wang J, Xiao H, Huang C, Wu C, Zhang L, Qian C, Xiang D. Targeting tumor-associated macrophages in colon cancer: mechanisms and therapeutic strategies. Front Immunol 2025; 16:1573917. [PMID: 40191202 PMCID: PMC11968422 DOI: 10.3389/fimmu.2025.1573917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 03/10/2025] [Indexed: 04/09/2025] Open
Abstract
Colon cancer (CC) remains a primary contributor to cancer-related fatalities worldwide, driven by difficulties in early diagnosis and constrained therapeutic options. Recent studies underscore the importance of the tumor microenvironment (TME), notably tumor-associated macrophages (TAMs), in fostering malignancy progression and therapy resistance. Through their inherent plasticity, TAMs facilitate immunosuppression, angiogenic processes, metastatic spread, and drug tolerance. In contrast to M1 macrophages, which promote inflammatory and tumoricidal responses, M2 macrophages support tumor expansion and dissemination by exerting immunosuppressive and pro-angiogenic influences. Consequently, manipulating TAMs has emerged as a potential avenue to enhance treatment effectiveness. This review outlines the origins, polarization states, and functions of TAMs in CC, highlights their role in driving tumor advancement, and surveys ongoing efforts to target these cells for better patient outcomes. Emerging therapeutic strategies aimed at modulating TAM functions - including depletion strategies, reprogramming approaches that shift M2-polarized TAMs toward an M1 phenotype, and inhibition of key signaling pathways sustaining TAM-mediated immunosuppression-are currently under active investigation. These approaches hold promise in overcoming TAM - induced resistance and improving immunotherapeutic efficacy in CC.
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Affiliation(s)
- Jianqin Xiang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Jian Wang
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Huihui Xiao
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Chengchen Huang
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Chunrong Wu
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Lin Zhang
- Department of Gastroenterology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Chenyuan Qian
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China
| | - Debing Xiang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Department of Oncology, Chongqing University Jiangjin Hospital, Chongqing, China
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Yagi T, Kagawa S, Nogi S, Taniguchi A, Yoshimoto M, Suemori K, Nagai Y, Fujita S, Kuroda S, Kikuchi S, Kakiuchi Y, Teraishi F, Takagi K, Ohara T, Tazawa H, Fujiwara T. Cancer-associated fibroblasts promote pro-tumor functions of neutrophils in pancreatic cancer via IL-8: potential suppression by pirfenidone. Cancer Immunol Immunother 2025; 74:96. [PMID: 39904796 PMCID: PMC11794937 DOI: 10.1007/s00262-025-03946-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 01/15/2025] [Indexed: 02/06/2025]
Abstract
BACKGROUND The mechanisms by which neutrophils acquire pro-tumor properties remain poorly understood. In pancreatic cancer, cancer-associated fibroblasts (CAFs) may interact with neutrophils, directing them to promote tumor progression. METHODS To validate the association between CAFs and neutrophils, the localization of neutrophils was examined in clinically resected pancreatic cancer specimens. CAFs were produced by culturing in cancer-conditioned media, and the effects of these CAFs on neutrophils were examined. In vitro migration and invasion assays assess the effect of CAF-activated neutrophils on cancer cells. The factors secreted by the activated neutrophils were also explored. Finally, pirfenidone (PFD) was tested to determine whether it could suppress the pro-tumor functions of activated neutrophils. RESULTS In pancreatic cancer specimens, neutrophils tended to co-localize with IL-6-positive CAFs. Neutrophils co-cultured with CAFs increased migratory capacity and prolonged life span. CAF-affected neutrophils enhance the migratory and invasive activities of pancreatic cancer cells. IL-8 is the most upregulated cytokine secreted by the neutrophils. PFD suppresses IL-8 secretion from CAF-stimulated neutrophils and mitigates the malignant traits of pancreatic cancer cells. CONCLUSION CAFs activate neutrophils and enhance the malignant phenotype of pancreatic cancer. The interactions between cancer cells, CAFs, and neutrophils can be disrupted by PFD, highlighting a potential therapeutic approach.
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Affiliation(s)
- Tomohiko Yagi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Shunsuke Kagawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan.
| | - Shohei Nogi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Atsuki Taniguchi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Masashi Yoshimoto
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Kanto Suemori
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Yasuo Nagai
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Shuto Fujita
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Shinji Kuroda
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
- Minimally Invasive Therapy Center, Okayama University Hospital, Okayama, Japan
| | - Satoru Kikuchi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Yoshihiko Kakiuchi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
- Minimally Invasive Therapy Center, Okayama University Hospital, Okayama, Japan
| | - Fuminori Teraishi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
- Minimally Invasive Therapy Center, Okayama University Hospital, Okayama, Japan
| | - Kosei Takagi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Toshiaki Ohara
- Departments of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroshi Tazawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
- Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
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6
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Zhao Y, Zhu W, Dong S, Zhang H, Zhou W. Glucose Metabolism Reprogramming of Immune Cells in the Microenvironment of Pancreatic and Hepatobiliary Cancers. J Gastroenterol Hepatol 2025; 40:355-366. [PMID: 39780341 DOI: 10.1111/jgh.16873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 12/22/2024] [Accepted: 12/26/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND AND AIM Pancreatic and hepatobiliary cancers are increasing in prevalence and contribute significantly to cancer-related mortality worldwide. Emerging therapeutic approaches, particularly immunotherapy, are gaining attention for their potential to harness the patient's immune system to combat these tumors. Understanding the role of immune cells in the tumor microenvironment (TME) and their metabolic reprogramming is key to developing more effective treatment strategies. This review aims to explore the relationship between immune cell function and glucose metabolism in the TME of pancreatic and hepatobiliary cancers. METHODS This review synthesizes current research on the metabolic adaptations of immune cells, specifically focusing on glucose metabolism within the TME of pancreatic and hepatobiliary cancers. We examine the mechanisms by which immune cells influence tumor progression through metabolic reprogramming and how these interactions can be targeted for therapeutic purposes. RESULTS Immune cells in the TME undergo significant metabolic changes, with glucose metabolism playing a central role in modulating immune responses. These metabolic shifts not only affect immune cell function but also influence tumor behavior and progression. The unique metabolic features of immune cells in pancreatic and hepatobiliary cancers provide new opportunities for targeting immune responses to combat these malignancies more effectively. CONCLUSION Understanding the complex relationship between immune cell glucose metabolism and tumor progression in the TME of pancreatic and hepatobiliary cancers offers promising therapeutic strategies. By modulating immune responses through targeted metabolic interventions, it may be possible to improve the efficacy of immunotherapies and better combat these aggressive cancers.
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Affiliation(s)
- Yongqing Zhao
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Weixiong Zhu
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Shi Dong
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Hui Zhang
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Wence Zhou
- The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- Gansu Province Key Laboratory of Environmental Oncology, Lanzhou, China
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7
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Glaviano A, Lau HSH, Carter LM, Lee EHC, Lam HY, Okina E, Tan DJJ, Tan W, Ang HL, Carbone D, Yee MYH, Shanmugam MK, Huang XZ, Sethi G, Tan TZ, Lim LHK, Huang RYJ, Ungefroren H, Giovannetti E, Tang DG, Bruno TC, Luo P, Andersen MH, Qian BZ, Ishihara J, Radisky DC, Elias S, Yadav S, Kim M, Robert C, Diana P, Schalper KA, Shi T, Merghoub T, Krebs S, Kusumbe AP, Davids MS, Brown JR, Kumar AP. Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition. J Hematol Oncol 2025; 18:6. [PMID: 39806516 PMCID: PMC11733683 DOI: 10.1186/s13045-024-01634-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 11/11/2024] [Indexed: 01/16/2025] Open
Abstract
The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.
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Affiliation(s)
- Antonino Glaviano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Hannah Si-Hui Lau
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Lukas M Carter
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - E Hui Clarissa Lee
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Hiu Yan Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Elena Okina
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Donavan Jia Jie Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, 139651, Singapore
| | - Wency Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, 139651, Singapore
| | - Hui Li Ang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Daniela Carbone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Michelle Yi-Hui Yee
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Xiao Zi Huang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Lina H K Lim
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, 117456, Singapore
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Ruby Yun-Ju Huang
- School of Medicine and Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan
- Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
| | - Hendrik Ungefroren
- First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, 23538, Lübeck, Germany
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, UMC, Vrije Universiteit, HV Amsterdam, 1081, Amsterdam, The Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, 56017, San Giuliano, Italy
| | - Dean G Tang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
- Experimental Therapeutics (ET) Graduate Program, University at Buffalo & Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Tullia C Bruno
- Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Mads Hald Andersen
- National Center for Cancer Immune Therapy, Department of Oncology, Herlev and Gentofte Hospital, Herlev, Denmark
| | - Bin-Zhi Qian
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, The Human Phenome Institute, Zhangjiang-Fudan International Innovation Center, Fudan University, Shanghai, China
| | - Jun Ishihara
- Department of Bioengineering, Imperial College London, London, W12 0BZ, UK
| | - Derek C Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Salem Elias
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Saurabh Yadav
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Minah Kim
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Caroline Robert
- Department of Cancer Medicine, Inserm U981, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France
- Faculty of Medicine, University Paris-Saclay, Kremlin Bicêtre, Paris, France
| | - Patrizia Diana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Kurt A Schalper
- Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, USA
| | - Tao Shi
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Taha Merghoub
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Department of Medicine, Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, NY, USA
| | - Simone Krebs
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anjali P Kusumbe
- Tissue and Tumor Microenvironment Group, MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Matthew S Davids
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jennifer R Brown
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
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Takemura K, Ikeda K, Miyake H, Sogame Y, Yasuda H, Okada N, Iwata K, Sakagami J, Yamaguchi K, Itoh Y, Umemura A. Epithelial-Mesenchymal Transition Suppression by ML210 Enhances Gemcitabine Anti-Tumor Effects on PDAC Cells. Biomolecules 2025; 15:70. [PMID: 39858464 PMCID: PMC11763895 DOI: 10.3390/biom15010070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 12/23/2024] [Accepted: 01/03/2025] [Indexed: 01/27/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. Neoadjuvant chemotherapy (NAC) has become a standard treatment for patients scheduled for surgical resection, but the high rate of postoperative recurrence is a critical problem. Optimization of NAC is desirable to reduce postoperative recurrence and achieve long-term survival. However, if a patient's general condition deteriorates due to NAC toxicity, surgical outcomes may be compromised. Therefore, we aimed to identify drug(s) that can be used in combination with gemcitabine (GEM), a drug widely used for the treatment of PDAC, to inhibit distant metastatic recurrence, particularly after surgery. After several screening steps, ML210, a low molecular weight chemical, was found to suppress the epithelial-mesenchymal transition (EMT) in PDAC cells in combination with GEM. Specifically, low dose ML210 in combination with GEM was sufficient for cell migration without apparent toxicity or cell death. Mechanistically, ML210, which was developed as a glutathione peroxidase 4 (GPX4) inhibitor to induce lipid peroxidation, increased the oxidized lipid concentrations in PDAC cells. The oxidization of the cell membrane lipids may suppress EMT, including cell migration. Since EMT is a major malignant phenotype of PDAC, our findings may lead to the advancement of PDAC therapy, especially in the prevention of postoperative recurrence.
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Affiliation(s)
- Keisuke Takemura
- Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (K.T.); (K.I.); (N.O.); (K.I.)
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.M.); (Y.S.); (H.Y.); (J.S.); (K.Y.); (Y.I.)
| | - Kyohei Ikeda
- Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (K.T.); (K.I.); (N.O.); (K.I.)
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.M.); (Y.S.); (H.Y.); (J.S.); (K.Y.); (Y.I.)
| | - Hayato Miyake
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.M.); (Y.S.); (H.Y.); (J.S.); (K.Y.); (Y.I.)
| | - Yoshio Sogame
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.M.); (Y.S.); (H.Y.); (J.S.); (K.Y.); (Y.I.)
| | - Hiroaki Yasuda
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.M.); (Y.S.); (H.Y.); (J.S.); (K.Y.); (Y.I.)
- Saiseikai Shiga Hospital, 2-4-1 Ohashi, Ritto 520-3046, Shiga, Japan
| | - Nobuhiro Okada
- Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (K.T.); (K.I.); (N.O.); (K.I.)
| | - Kazumi Iwata
- Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (K.T.); (K.I.); (N.O.); (K.I.)
| | - Junichi Sakagami
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.M.); (Y.S.); (H.Y.); (J.S.); (K.Y.); (Y.I.)
- Fukuchiyama City Hospital, 231 Atsunaka-cho, Fukuchiyama 620-8505, Kyoto, Japan
| | - Kanji Yamaguchi
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.M.); (Y.S.); (H.Y.); (J.S.); (K.Y.); (Y.I.)
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (H.M.); (Y.S.); (H.Y.); (J.S.); (K.Y.); (Y.I.)
| | - Atsushi Umemura
- Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; (K.T.); (K.I.); (N.O.); (K.I.)
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Dong B, Zhang Y, Gao H, Liu J, Li J. Machine Learning Developed a MYC Expression Feature-Based Signature for Predicting Prognosis and Chemoresistance in Pancreatic Adenocarcinoma. Biochem Genet 2024; 62:4191-4214. [PMID: 38245886 DOI: 10.1007/s10528-023-10625-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 12/07/2023] [Indexed: 01/23/2024]
Abstract
MYC has been identified to profoundly influence a wide range of pathologic processes in cancers. However, the prognostic value of MYC-related genes in pancreatic adenocarcinoma (PAAD) remains unclarified. Gene expression data and clinical information of PAAD patients were obtained from The Cancer Genome Atlas (TCGA) database (training set). Validation sets included GSE57495, GSE62452, and ICGC-PACA databases. LASSO regression analysis was used to develop a risk signature for survival prediction. Single-cell sequencing data from GSE154778 and CRA001160 datasets were analyzed. Functional studies were conducted using siRNA targeting RHOF and ITGB6 in PANC-1 cells. High MYC expression was found to be significantly associated with a poor prognosis in patients with PAAD. Additionally, we identified seven genes (ADGRG6, LINC00941, RHOF, SERPINB5, INSYN2B, ITGB6, and DEPDC1) that exhibited a strong correlation with both MYC expression and patient survival. They were then utilized to establish a risk model (MYCsig), which showed robust predictive ability. Furthermore, MYCsig demonstrated a positive correlation with the expression of HLA genes and immune checkpoints, as well as the chemotherapy response of PAAD. RHOF and ITGB6, expressed mainly in malignant cells, were identified as key oncogenes regulating chemosensitivity through EMT. Downregulation of RHOF and ITGB6 reduced cell proliferation and invasion in PANC-1 cells. The developed MYCsig demonstrates its potential in enhancing the management of patients with PAAD by facilitating risk assessment and predicting response to adjuvant chemotherapy. Additionally, our study identifies RHOF and ITGB6 as novel oncogenes linked to EMT and chemoresistance in PAAD.
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Affiliation(s)
- Biao Dong
- Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Shijiazhuang, 050000, Hebei, China
| | - Yueshan Zhang
- Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Shijiazhuang, 050000, Hebei, China
| | - Han Gao
- Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Shijiazhuang, 050000, Hebei, China
| | - Jia Liu
- Department of Precision Medicine, Accb Biotech. Ltd, Beijing, China
| | - Jiankun Li
- Department of Hepatobiliary Surgery, Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Shijiazhuang, 050000, Hebei, China.
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Wang C, Xu S, Qin Y. Tumor-derived exosome PPP3CB induce gemcitabine resistance by regulating miR-298/STAT3 in pancreatic cancer. Heliyon 2024; 10:e36434. [PMID: 39253142 PMCID: PMC11381791 DOI: 10.1016/j.heliyon.2024.e36434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 08/14/2024] [Accepted: 08/15/2024] [Indexed: 09/11/2024] Open
Abstract
Purpose Due to resistance to gemcitabine (GEM), patients with pancreatic cancer (PC) usually have poor prognosis and low survival rate. The purpose of our research was to explore the impact of exosome PPP3CB on GEM resistance in PC, and concurrently analyze the regulatory role of the miR-298/STAT3 signaling pathway. Methods Exosomes isolated from PC cells were verified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting (WB). The interaction between PPP3CB and miR-298 was verified using dual-luciferase reporter gene assay, followed by evaluation of cell growth and death using CCK8 assay, EdU staining, and flow cytometry. Results Increased PPP3CB expression was observed in GEM-resistant PC cells. Exosomes from PC cells and GEM-resistant PC cells were successfully extracted by ultra-high speed centrifugation. Confocal microscopy showed internalization of fluorescein amide (FAM)-labeled GEM-resistant exosomes by PC cells. PPP3CB enhanced the proliferation of GEM-resistant PC cells and inhibited their apoptosis, whereas down-regulation of PPP3CB promoted the death of PC cells and inhibited the proliferation of GEM-resistant PC cells, and enhance the susceptibility of PC cells to GEM. Additionally, PPP3CB positively regulated STAT3 expression in PC cells by down-regulating miR-298, thus promoting the growth and inhibiting the death of PC cells. Conclusion PC cell-derived exosome PPP3CB enhances STAT3 expression by downregulating miR-298, stimulating cell growth, and suppressing cell death, thereby increasing the resistance of PC cells to GEM.
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Affiliation(s)
- Chaojun Wang
- Department of Ultrasound, Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang, 323000, China
| | - Shengqian Xu
- Department of Hepatobiliary Pancreatic Surgery, Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang, 323000, China
| | - Yong Qin
- Department of Hepatobiliary Pancreatic Surgery, Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang, 323000, China
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11
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Lei W, Wang W, Qin S, Yao W. Predictive value of inflammation and nutritional index in immunotherapy for stage IV non-small cell lung cancer and model construction. Sci Rep 2024; 14:17511. [PMID: 39080372 PMCID: PMC11289435 DOI: 10.1038/s41598-024-66813-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 07/04/2024] [Indexed: 08/02/2024] Open
Abstract
Identifying individuals poised to gain from immune checkpoint inhibitor (ICI) therapies is a pivotal element in the realm of tailored healthcare. The expression level of Programmed Death Ligand 1 (PD-L1) has been linked to the response to ICI therapy, but its assessment typically requires substantial tumor tissue, which can be challenging to obtain. In contrast, blood samples are more feasible for clinical application. A number of promising peripheral biomarkers have been proposed to overcome this hurdle. This research aims to evaluate the prognostic utility of the albumin-to-lactate dehydrogenase ratio (LAR), the Pan-immune-inflammation Value (PIV), and the Prognostic Nutritional Index (PNI) in predicting the response to ICI therapy in individuals with advanced non-small cell lung cancer (NSCLC). Furthermore, the study seeks to construct a predictive nomogram that includes these markers to facilitate the selection of patients with a higher likelihood of benefiting from ICI therapy. A research initiative scrutinized the treatment records of 157 advanced NSCLC patients who received ICI therapy across two Jiangxi medical centers. The cohort from Jiangxi Provincial People's Hospital (comprising 108 patients) was utilized for the training dataset, while the contingent from Jiangxi Cancer Hospital (49 patients) served for validation purposes. Stratification was based on established LAR, PIV, and PNI benchmarks to explore associations with DCR and ORR metrics. Factorial influences on ICI treatment success were discerned through univariate and multivariate Cox regression analysis. Subsequently, a Nomogram was devised to forecast outcomes, its precision gauged by ROC and calibration curves, DCA analysis, and cross-institutional validation. In the training group, the optimal threshold values for LAR, PIV, and PNI were identified as 5.205, 297.49, and 44.6, respectively. Based on these thresholds, LAR, PIV, and PNI were categorized into high (≥ Cut-off) and low (< Cut-off) groups. Patients with low LAR (L-LAR), low PIV (L-PIV), and high PNI (H-PNI) exhibited a higher disease control rate (DCR) (P < 0.05) and longer median progression-free survival (PFS) (P < 0.05). Cox multivariate analysis indicated that PS, malignant pleural effusion, liver metastasis, high PIV (H-PIV), and low PNI (L-PNI) were risk factors adversely affecting the efficacy of immunotherapy (P < 0.05). The Nomogram model predicted a concordance index (C-index) of 0.78 (95% CI: 0.73-0.84). The areas under the ROC curve (AUC) for the training group at 6, 9, and 12 months were 0.900, 0.869, and 0.866, respectively, while the AUCs for the external validation group at the same time points were 0.800, 0.886, and 0.801, respectively. Throughout immunotherapy, PIV and PNI could act as prospective indicators for forecasting treatment success in NSCLC patients, while the devised Nomogram model exhibits strong predictive performance for patient prognoses.
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Affiliation(s)
- Wenqian Lei
- Graduate School, Jiangxi Medical College, Nanchang University, 461 Bayi Avenue, Donghu District, Nanchang, 330006, Jiangxi, China
| | - Wei Wang
- Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Wenzhou Medical University, 270 Xueyuanxi Road, Lucheng District, Wenzhou, 325027, Zhejiang, China
| | - Shixiang Qin
- Graduate School, Bengbu Medical University, Bengbu, 233030, Anhui, China
| | - Weirong Yao
- Graduate School, Jiangxi Medical College, Nanchang University, 461 Bayi Avenue, Donghu District, Nanchang, 330006, Jiangxi, China.
- Department of Oncology, Jiangxi Provincial People's Hospital, 152 Aiguo Road, Nanchan, 330006, Jiangxi, China.
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Shan Y, Yu M, Dai H, Zhu X, Wang F, You Y, Cao H, Sheng L, Zhao J, Tang L, Shi J, Sheng M. The role of macrophage-derived Exosomes in reversing peritoneal fibrosis: Insights from Astragaloside IV. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155683. [PMID: 38701543 DOI: 10.1016/j.phymed.2024.155683] [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: 12/25/2023] [Revised: 04/06/2024] [Accepted: 04/24/2024] [Indexed: 05/05/2024]
Abstract
BACKGROUND Peritoneal dialysis (PD) is a successful renal replacement therapy for end-stage renal disease. Long-term PD causes mesothelial-mesenchymal transition (MMT) of peritoneal mesothelial cells (PMCs), leading to peritoneal fibrosis (PF), which reduces the efficiency of PD. Macrophages are thought to play a role in the onset and perpetuation of peritoneal injury. However, the mechanisms by which macrophages-PMCs communication regulates peritoneal fibrosis are not fully understood resulting in a lack of disease-modifying drugs. Astragaloside IV (AS-IV) possessed anti-fibrotic effect towards PF in PD whereas the mechanistic effect of AS-IV in PD is unknown. METHODS The primary macrophages were extracted and treated with LPS or AS-IV, then co-cultured with primary PMCs in transwell plates. The macrophage-derived exosomes were extracted and purified by differential centrifugation, then co-cultured with primary PMCs. Small RNA-seq was used to detect differential miRNAs in exosomes, and then KEGG analysis and q-PCR were performed for validation. In vivo PD rat models were established by inducing with high-glucose peritoneal dialysis fluid and different concentrations of AS-IV and exosomes were intraperitoneal injection. Through qRT-PCR, western blotting, and luciferase reporting, candidate proteins and pathways were validated in vivo and in vitro. The functions of the validated pathways were further investigated using the mimic or inhibition strategy. PF and inflammatory situations were assessed. RESULTS We found AS-IV reversed the MMT of PMCs caused by LPS-stimulated macrophages and the improving effect was mediated by macrophage-derived exosomes in vitro. We also demonstrated that AS-IV significantly reduced the MMT of PMCs in vitro or PF in a rat PD model via regulating exosome-contained miR-204-5p which targets Foxc1/β-catenin signaling pathway. CONCLUSION AS-IV attenuates macrophage-derived exosomes induced fibrosis in PD through the miR-204-5p/Foxc1 pathway.
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Affiliation(s)
- Yun Shan
- Department of nephrology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China,; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Manshu Yu
- Department of nephrology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
| | - Huibo Dai
- Department of nephrology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China,; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xiaolin Zhu
- Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Funing Wang
- Department of nephrology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China,; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yongqing You
- Department of nephrology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China,; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Huimin Cao
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Li Sheng
- Department of nephrology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China,; Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Junyi Zhao
- Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Lei Tang
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jun Shi
- Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Meixiao Sheng
- Department of nephrology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China,.
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Armando F, Porcellato I, de Paolis L, Mecocci S, Passeri B, Ciurkiewicz M, Mechelli L, Grazia De Ciucis C, Pezzolato M, Fruscione F, Brachelente C, Montemurro V, Cappelli K, Puff C, Baumgärtner W, Ghelardi A, Razzuoli E. Vulvo-vaginal epithelial tumors in mares: A preliminary investigation on epithelial-mesenchymal transition and tumor-immune microenvironment. Vet Pathol 2024; 61:366-381. [PMID: 37909398 DOI: 10.1177/03009858231207025] [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] [Indexed: 11/03/2023]
Abstract
Vulvo-vaginal epithelial tumors are uncommon in mares, and data on the epithelial-to-mesenchymal transition (EMT) and the tumor-immune microenvironment (TIME) are still lacking. This is a study investigating the equus caballus papillomavirus type 2 (EcPV2) infection state as well as the EMT process and the tumor microenvironment in vulvo-vaginal preneoplastic/ benign (8/22) or malignant (14/22) epithelial lesions in mares. To do this, histopathological, immunohistochemical, transcriptomic, in situ hybridization, and correlation analyses were carried out. Immunohistochemistry quantification showed that cytoplasmic E-cadherin and β-catenin expression as well as nuclear β-catenin expression were features of malignant lesions, while benign/preneoplastic lesions were mainly characterized by membranous E-cadherin and β-catenin expression. Despite this, there were no differences between benign and malignant equine vulvo-vaginal lesions in the expression of downstream genes involved in the canonical and noncanonical wnt/β-catenin pathways. In addition, malignant lesions were characterized by a lower number of cells with cytoplasmic cytokeratin expression as well as a slightly higher cytoplasmic vimentin immunolabeling. The TIME of malignant lesions was characterized by more numerous CD204+ M2-polarized macrophages. Altogether, our results support the hypothesis that some actors in TIME such as CD204+ M2-polarized macrophages may favor the EMT process in equine vulvo-vaginal malignant lesions providing new insights for future investigations in the field of equine EcPV2-induced genital neoplastic lesions.
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Affiliation(s)
| | | | - Livia de Paolis
- University of Perugia, Perugia, Italy
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D'Aosta, Genova, Italy
| | | | | | | | | | - Chiara Grazia De Ciucis
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D'Aosta, Genova, Italy
- University of Pavia, Pavia, Italy
| | - Marzia Pezzolato
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D'Aosta, Genova, Italy
| | - Floriana Fruscione
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D'Aosta, Genova, Italy
| | | | - Vittoria Montemurro
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D'Aosta, Genova, Italy
| | | | - Christina Puff
- University of Veterinary Medicine Hannover, Hannover, Germany
| | | | | | - Elisabetta Razzuoli
- Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle D'Aosta, Genova, Italy
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Rakina M, Larionova I, Kzhyshkowska J. Macrophage diversity in human cancers: New insight provided by single-cell resolution and spatial context. Heliyon 2024; 10:e28332. [PMID: 38571605 PMCID: PMC10988020 DOI: 10.1016/j.heliyon.2024.e28332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 03/15/2024] [Accepted: 03/15/2024] [Indexed: 04/05/2024] Open
Abstract
M1/M2 paradigm of macrophage plasticity has existed for decades. Now it becomes clear that this dichotomy doesn't adequately reflect the diversity of macrophage phenotypes in tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are a major population of innate immune cells in the TME that promotes tumor cell proliferation, angiogenesis and lymphangiogenesis, invasion and metastatic niche formation, as well as response to anti-tumor therapy. However, the fundamental restriction in therapeutic TAM targeting is the limited knowledge about the specific TAM states in distinct human cancer types. Here we summarized the results of the most recent studies that use advanced technologies (e.g. single-cell RNA sequencing and spatial transcriptomics) allowing to decipher novel functional subsets of TAMs in numerous human cancers. The transcriptomic profiles of these TAM subsets and their clinical significance were described. We emphasized the characteristics of specific TAM subpopulations - TREM2+, SPP1+, MARCO+, FOLR2+, SIGLEC1+, APOC1+, C1QC+, and others, which have been most extensively characterized in several cancers, and are associated with cancer prognosis. Spatial transcriptomics technologies defined specific spatial interactions between TAMs and other cell types, especially fibroblasts, in tumors. Spatial transcriptomics methods were also applied to identify markers of immunotherapy response, which are expressed by macrophages or in the macrophage-abundant regions. We highlighted the perspectives for novel techniques that utilize spatial and single cell resolution in investigating new ligand-receptor interactions for effective immunotherapy based on TAM-targeting.
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Affiliation(s)
- Militsa Rakina
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, 634050, Russia
- Laboratory of Molecular Therapy of Cancer, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, 634009, Russia
| | - Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, 634050, Russia
- Laboratory of Molecular Therapy of Cancer, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, 634009, Russia
| | - Julia Kzhyshkowska
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, 634050, Russia
- Institute of Transfusion Medicine and Immunology, Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, 68167, Germany
- German Red Cross Blood Service Baden-Württemberg – Hessen, Mannheim, 68167, Germany
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15
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Toledo B, Deiana C, Scianò F, Brandi G, Marchal JA, Perán M, Giovannetti E. Treatment resistance in pancreatic and biliary tract cancer: molecular and clinical pharmacology perspectives. Expert Rev Clin Pharmacol 2024; 17:323-347. [PMID: 38413373 DOI: 10.1080/17512433.2024.2319340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 02/12/2024] [Indexed: 02/29/2024]
Abstract
INTRODUCTION Treatment resistance poses a significant obstacle in oncology, especially in biliary tract cancer (BTC) and pancreatic cancer (PC). Current therapeutic options include chemotherapy, targeted therapy, and immunotherapy. Resistance to these treatments may arise due to diverse molecular mechanisms, such as genetic and epigenetic modifications, altered drug metabolism and efflux, and changes in the tumor microenvironment. Identifying and overcoming these mechanisms is a major focus of research: strategies being explored include combination therapies, modulation of the tumor microenvironment, and personalized approaches. AREAS COVERED We provide a current overview and discussion of the most relevant mechanisms of resistance to chemotherapy, target therapy, and immunotherapy in both BTC and PC. Furthermore, we compare the different strategies that are being implemented to overcome these obstacles. EXPERT OPINION So far there is no unified theory on drug resistance and progress is limited. To overcome this issue, individualized patient approaches, possibly through liquid biopsies or single-cell transcriptome studies, are suggested, along with the potential use of artificial intelligence, to guide effective treatment strategies. Furthermore, we provide insights into what we consider the most promising areas of research, and we speculate on the future of managing treatment resistance to improve patient outcomes.
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Affiliation(s)
- Belén Toledo
- Department of Health Sciences, University of Jaén, Jaén, Spain
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, The Netherlands
| | - Chiara Deiana
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Fabio Scianò
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, The Netherlands
- Lumobiotics GmbH, Karlsruhe, Germany
| | - Giovanni Brandi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Juan Antonio Marchal
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Instituto de Investigación Sanitaria ibs. GRANADA, Hospitales Universitarios de Granada-Universidad de Granada, Granada, Spain
- Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, Spain
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, Spain
| | - Macarena Perán
- Department of Health Sciences, University of Jaén, Jaén, Spain
- Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research (CIBM), University of Granada, Granada, Spain
- Excellence Research Unit "Modeling Nature" (MNat), University of Granada, Granada, Spain
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, The Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, Pisa, Italy
- Cancer Pharmacology Lab, Associazione Italiana per la Ricerca sul Cancro (AIRC) Start-Up Unit, Fondazione Pisana per la Scienza, University of Pisa, Pisa, Italy
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16
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Zhang J, Wang Y, Wang L, You L, Zhang T. Pancreatic ductal adenocarcinoma chemoresistance: From metabolism reprogramming to novel treatment. Chin Med J (Engl) 2024; 137:408-420. [PMID: 37545027 PMCID: PMC10876258 DOI: 10.1097/cm9.0000000000002758] [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: 03/28/2023] [Indexed: 08/08/2023] Open
Abstract
ABSTRACT As pancreatic cancer (PC) is highly malignant, its patients tend to develop metastasis at an early stage and show a poor response to conventional chemotherapies. First-line chemotherapies for PC, according to current guidelines, include fluoropyrimidine- and gemcitabine-based regimens. Accumulating research on drug resistance has shown that biochemical metabolic aberrations in PC, especially those involving glycolysis and glutamine metabolism, are highly associated with chemoresistance. Additionally, lipid metabolism is a major factor in chemoresistance. However, emerging compounds that target these key metabolic pathways have the potential to overcome chemoresistance. This review summarizes how PC develops chemoresistance through aberrations in biochemical metabolism and discusses novel critical targets and pathways within cancer metabolism for new drug research.
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Affiliation(s)
- Jingcheng Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yutong Wang
- Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Lejunzi Wang
- Department of Anaesthesia, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
- Clinical Immunology Centre, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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17
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Elfstrum AK, Bapat AS, Schwertfeger KL. Defining and targeting macrophage heterogeneity in the mammary gland and breast cancer. Cancer Med 2024; 13:e7053. [PMID: 38426622 PMCID: PMC10905685 DOI: 10.1002/cam4.7053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 02/09/2024] [Accepted: 02/16/2024] [Indexed: 03/02/2024] Open
Abstract
INTRODUCTION Macrophages are innate immune cells that are associated with extensive phenotypic and functional plasticity and contribute to normal development, tissue homeostasis, and diseases such as cancer. In this review, we discuss the heterogeneity of tissue resident macrophages in the normal mammary gland and tumor-associated macrophages in breast cancer. Tissue resident macrophages are required for mammary gland development, where they have been implicated in promoting extracellular matrix remodeling, apoptotic clearance, and cellular crosstalk. In the context of cancer, tumor-associated macrophages are key drivers of growth and metastasis via their ability to promote matrix remodeling, angiogenesis, lymphangiogenesis, and immunosuppression. METHOD We identified and summarized studies in Pubmed that describe the phenotypic and functional heterogeneity of macrophages and the implications of targeting individual subsets, specifically in the context of mammary gland development and breast cancer. We also identified and summarized recent studies using single-cell RNA sequencing to identify and describe macrophage subsets in human breast cancer samples. RESULTS Advances in single-cell RNA sequencing technologies have yielded nuances in macrophage heterogeneity, with numerous macrophage subsets identified in both the normal mammary gland and breast cancer tissue. Macrophage subsets contribute to mammary gland development and breast cancer progression in differing ways, and emerging studies highlight a role for spatial localization in modulating their phenotype and function. CONCLUSION Understanding macrophage heterogeneity and the unique functions of each subset in both normal mammary gland development and breast cancer progression may lead to more promising targets for the treatment of breast cancer.
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Affiliation(s)
- Alexis K. Elfstrum
- Microbiology, Immunology, and Cancer Biology Graduate ProgramUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Aditi S. Bapat
- Molecular Pharmacology and Therapeutics Graduate ProgramUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Kathryn L. Schwertfeger
- Department of Laboratory Medicine and PathologyUniversity of MinnesotaMinneapolisMinnesotaUSA
- Masonic Cancer CenterUniversity of MinnesotaMinneapolisMinnesotaUSA
- Center for ImmunologyUniversity of MinnesotaMinneapolisMinnesotaUSA
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18
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Rismanbaf A. Improving targeted small molecule drugs to overcome chemotherapy resistance. Cancer Rep (Hoboken) 2024; 7:e1945. [PMID: 37994401 PMCID: PMC10809209 DOI: 10.1002/cnr2.1945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 10/25/2023] [Accepted: 11/12/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Conventional cancer treatments face the challenge of therapeutic resistance, which causes poor treatment outcomes. The use of combination therapies can improve treatment results in patients and is one of the solutions to overcome this challenge. Chemotherapy is one of the conventional treatments that, due to the non-targeted and lack of specificity in targeting cancer cells, can cause serious complications in the short and long-term for patients by damaging healthy cells. Also, the employment of a wide range of strategies for chemotherapy resistance by cancer cells, metastasis, and cancer recurrence create serious problems to achieve the desired results of chemotherapy. Accordingly, targeted therapies can be used as a combination treatment with chemotherapy to both cause less damage to healthy cells, which as a result, they reduce the side effects of chemotherapy, and by targeting the factors that cause therapeutic challenges, can improve the results of chemotherapy in patients. RECENT FINDINGS Small molecules are one of the main targeted therapies that can be used for diverse targets in cancer treatment due to their penetration ability and characteristics. However, small molecules in cancer treatment are facing obstacles that a better understanding of cancer biology, as well as the mechanisms and factors involved in chemotherapy resistance, can lead to the improvement of this type of major targeted therapy. CONCLUSION In this review article, at first, the challenges that lead to not achieving the desired results in chemotherapy and how cancer cells can be resistant to chemotherapy are examined, and at the end, research areas are suggested that more focusing on them, can lead to the improvement of the results of using targeted small molecules as an adjunctive treatment for chemotherapy in the conditions of chemotherapy resistance and metastasis of cancer cells.
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Affiliation(s)
- Amirhossein Rismanbaf
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical SciencesIslamic Azad UniversityTehranIran
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19
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Sumitomo R, Menju T, Shimazu Y, Toyazaki T, Chiba N, Miyamoto H, Hirayama Y, Nishikawa S, Tanaka S, Yutaka Y, Yamada Y, Nakajima D, Ohsumi A, Hamaji M, Sato A, Yoshizawa A, Huang C, Haga H, Date H. M2-like tumor-associated macrophages promote epithelial-mesenchymal transition through the transforming growth factor β/Smad/zinc finger e-box binding homeobox pathway with increased metastatic potential and tumor cell proliferation in lung squamous cell carcinoma. Cancer Sci 2023; 114:4521-4534. [PMID: 37806311 PMCID: PMC10728010 DOI: 10.1111/cas.15987] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 08/18/2023] [Accepted: 09/19/2023] [Indexed: 10/10/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) promotes primary tumor progression toward a metastatic state. The role of tumor-associated macrophages (TAMs) in inducing EMT in lung squamous cell carcinoma (LUSC) remains unclear. We aimed to clarify the significance of TAMs in relation to EMT in LUSC. We collected 221 LUSC specimens from patients who had undergone surgery. Immunohistochemistry was performed to evaluate M1-like and M2-like TAM distribution and EMT by E-cadherin and vimentin staining. Human LUSC cell lines (H226 and EBC-1) and a human monocyte cell line (THP-1) were used for in vitro experiments. M2-like polarization of TAMs and EMT marker expression in LUSC cells were evaluated by western blotting. The biological behavior of LUSC cells was evaluated by migration, invasion, and cell proliferation assays. Immunohistochemical analysis showed that 166 (75.1%) tumors were E-cadherin-positive and 44 (19.9%) were vimentin-positive. M2-like TAM density in the tumor stroma was significantly associated with vimentin positivity and worse overall survival. Western blotting demonstrated higher levels of CD163, CD206, vascular endothelial growth factor, and transforming growth factor beta 1 (TGF-β1) in TAMs versus unstimulated macrophages. Furthermore, increased TGF-β1 secretion from TAMs was confirmed by ELISA. TAM-co-cultured H226 and EBC-1 cells exhibited EMT (decreased E-cadherin, increased vimentin). Regarding EMT-activating transcriptional factors, phosphorylated Smad3 and ZEB-family proteins were higher in TAM-co-cultured LUSC cells than in parental cells. TAM-co-cultured H226 and EBC-1 cells demonstrated enhanced migration and invasion capabilities and improved proliferation. Overall, the present study suggests that TAMs can induce EMT with increased metastatic potential and tumor cell proliferation in LUSC.
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Affiliation(s)
- Ryota Sumitomo
- Department of Thoracic Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
- Department of Thoracic SurgeryTazuke Kofukai Medical Research Institute, Kitano HospitalOsakaJapan
| | - Toshi Menju
- Department of Thoracic Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Yumeta Shimazu
- Department of Thoracic Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Toshiya Toyazaki
- Department of Thoracic Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Naohisa Chiba
- Department of Thoracic Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Hideaki Miyamoto
- Department of Thoracic Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Yutaka Hirayama
- Department of Respiratory Medicine, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Shigeto Nishikawa
- Department of Thoracic Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Satona Tanaka
- Department of Thoracic Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Yojiro Yutaka
- Department of Thoracic Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Yoshito Yamada
- Department of Thoracic Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Daisuke Nakajima
- Department of Thoracic Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Akihiro Ohsumi
- Department of Thoracic Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Masatsugu Hamaji
- Department of Thoracic Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Atsuyasu Sato
- Department of Respiratory Medicine, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Akihiko Yoshizawa
- Department of Diagnostic PathologyKyoto University HospitalKyotoJapan
| | - Cheng‐Long Huang
- Department of Thoracic SurgeryTazuke Kofukai Medical Research Institute, Kitano HospitalOsakaJapan
| | - Hironori Haga
- Department of Diagnostic PathologyKyoto University HospitalKyotoJapan
| | - Hiroshi Date
- Department of Thoracic Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
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20
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Wei L, Sun J, Wang X, Huang Y, Huang L, Han L, Zheng Y, Xu Y, Zhang N, Yang M. Noncoding RNAs: an emerging modulator of drug resistance in pancreatic cancer. Front Cell Dev Biol 2023; 11:1226639. [PMID: 37560164 PMCID: PMC10407809 DOI: 10.3389/fcell.2023.1226639] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/17/2023] [Indexed: 08/11/2023] Open
Abstract
Pancreatic cancer is the eighth leading cause of cancer-related deaths worldwide. Chemotherapy including gemcitabine, 5-fluorouracil, adriamycin and cisplatin, immunotherapy with immune checkpoint inhibitors and targeted therapy have been demonstrated to significantly improve prognosis of pancreatic cancer patients with advanced diseases. However, most patients developed drug resistance to these therapeutic agents, which leading to shortened patient survival. The detailed molecular mechanisms contributing to pancreatic cancer drug resistance remain largely unclear. The growing evidences have shown that noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are involved in pancreatic cancer pathogenesis and development of drug resistance. In the present review, we systematically summarized the new insight on of various miRNAs, lncRNAs and circRNAs on drug resistance of pancreatic cancer. These results demonstrated that targeting the tumor-specific ncRNA may provide novel options for pancreatic cancer treatments.
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Affiliation(s)
- Ling Wei
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jujie Sun
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xingwu Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yizhou Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Linying Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Linyu Han
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yanxiu Zheng
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yuan Xu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
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21
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Lin HJ, Liu Y, Caroland K, Lin J. Polarization of Cancer-Associated Macrophages Maneuver Neoplastic Attributes of Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2023; 15:3507. [PMID: 37444617 DOI: 10.3390/cancers15133507] [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: 05/31/2023] [Revised: 07/01/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Mounting evidence links the phenomenon of enhanced recruitment of tumor-associated macrophages towards cancer bulks to neoplastic growth, invasion, metastasis, immune escape, matrix remodeling, and therapeutic resistance. In the context of cancer progression, naïve macrophages are polarized into M1 or M2 subtypes according to their differentiation status, gene signatures, and functional roles. While the former render proinflammatory and anticancer effects, the latter subpopulation elicits an opposite impact on pancreatic ductal adenocarcinoma. M2 macrophages have gained increasing attention as they are largely responsible for molding an immune-suppressive landscape. Through positive feedback circuits involving a paracrine manner, M2 macrophages can be amplified by and synergized with neighboring neoplastic cells, fibroblasts, endothelial cells, and non-cell autonomous constituents in the microenvironmental niche to promote an advanced disease state. This review delineates the molecular cues expanding M2 populations that subsequently convey notorious clinical outcomes. Future therapeutic regimens shall comprise protocols attempting to abolish environmental niches favoring M2 polarization; weaken cancer growth typically assisted by M2; promote the recruitment of tumoricidal CD8+ T lymphocytes and dendritic cells; and boost susceptibility towards gemcitabine as well as other chemotherapeutic agents.
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Affiliation(s)
- Huey-Jen Lin
- Department of Medical & Molecular Sciences, University of Delaware, Willard Hall Education Building, 16 West Main Street, Newark, DE 19716, USA
| | - Yingguang Liu
- Department of Molecular and Cellular Sciences, College of Osteopathic Medicine, Liberty University, 306 Liberty View Lane, Lynchburg, VA 24502, USA
| | - Kailey Caroland
- Department of Biochemistry and Molecular Biology, Molecular Medicine Graduate Program, Greenebaum Comprehensive Cancer Center, School of Medicine, University of Maryland, 108 N. Greene Street, Baltimore, MD 21201, USA
| | - Jiayuh Lin
- Department of Biochemistry and Molecular Biology, Molecular Medicine Graduate Program, Greenebaum Comprehensive Cancer Center, School of Medicine, University of Maryland, 108 N. Greene Street, Baltimore, MD 21201, USA
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22
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Hao J, Zhou C, Wang Z, Ma Z, Wu Z, Lv Y, Wu R. An amino acid metabolism-based seventeen-gene signature correlates with the clinical outcome and immune features in pancreatic cancer. Front Genet 2023; 14:1084275. [PMID: 37333498 PMCID: PMC10272610 DOI: 10.3389/fgene.2023.1084275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 05/09/2023] [Indexed: 06/20/2023] Open
Abstract
Background: Pancreatic cancer is an aggressive tumor with a low 5-year survival rate and primary resistance to most therapy. Amino acid (AA) metabolism is highly correlated with tumor growth, crucial to the aggressive biological behavior of pancreatic cancer; nevertheless, the comprehensive predictive significance of genes that regulate AA metabolism in pancreatic cancer remains unknown. Methods: The mRNA expression data downloaded from The Cancer Genome Atlas (TCGA) were derived as the training cohort, and the GSE57495 cohort from Gene Expression Omnibus (GEO) database was applied as the validation cohort. Random survival forest (RSF) and the least absolute shrinkage and selection operator (LASSO) regression analysis were employed to screen genes and construct an AA metabolism-related risk signature (AMRS). Kaplan-Meier analysis and receiver operating characteristic (ROC) curve were performed to assess the prognostic value of AMRS. We performed genomic alteration analysis and explored the difference in tumor microenvironment (TME) landscape associated with KRAS and TP53 mutation in both high- and low-AMRS groups. Subsequently, the relationships between AMRS and immunotherapy and chemotherapy sensitivity were evaluated. Results: A 17-gene AA metabolism-related risk model in the TCGA cohort was constructed according to RSF and LASSO. After stratifying patients into high- and low-AMRS groups based on the optimal cut-off value, we found that high-AMRS patients had worse overall survival (OS) in the training cohort (a median OS: 13.1 months vs. 50.1 months, p < 0.0001) and validation cohort (a median OS: 16.2 vs. 30.5 months, p = 1e-04). Genetic mutation analysis revealed that KRAS and TP53 were significantly more mutated in high-AMRS group, and patients with KRAS and TP53 alterations had significantly higher risk scores than those without. Based on the analysis of TME, low-AMRS group displayed significantly higher immune score and more enrichment of T Cell CD8+ cells. In addition, high-AMRS-group exhibited higher TMB and significantly lower tumor immune dysfunction and exclusion (TIDE) score and T Cells dysfunction score, which suggested a higher sensitive to immunotherapy. Moreover, high-AMRS group was also more sensitive to paclitaxel, cisplatin, and docetaxel. Conclusion: Overall, we constructed an AA-metabolism prognostic model, which provided a powerful prognostic predictor for the clinical treatment of pancreatic cancer.
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Affiliation(s)
- Jie Hao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Cancan Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zhenhua Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yi Lv
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Rongqian Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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23
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Deng Y, Fu Y, Chua SL, Khoo BL. Biofilm Potentiates Cancer-Promoting Effects of Tumor-Associated Macrophages in a 3D Multi-Faceted Tumor Model. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2205904. [PMID: 36748304 DOI: 10.1002/smll.202205904] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 01/01/2023] [Indexed: 05/11/2023]
Abstract
Components of the tumor microenvironment (TME), such as tumor-associated macrophages (TAMs), influence tumor progression. The specific polarization and phenotypic transition of TAMs in the tumor microenvironment lead to two-pronged impacts that can promote or hinder cancer development and treatment. Here, a novel microfluidic multi-faceted bladder tumor model (TAMPIEB ) is developed incorporating TAMs and cancer cells to evaluate the impact of bacterial distribution on immunomodulation within the tumor microenvironment in vivo. It is demonstrated for the first time that biofilm-induced inflammatory conditions within tumors promote the transition of macrophages from a pro-inflammatory M1-like to an anti-inflammatory/pro-tumor M2-like state. Consequently, multiple roles and mechanisms by which biofilms promote cancer by inducing pro-tumor phenotypic switch of TAMs are identified, including cancer hallmarks such as reducing susceptibility to apoptosis, enhancing cell viability, and promoting epithelial-mesenchymal transition and metastasis. Furthermore, biofilms formed by extratumoral bacteria can shield tumors from immune attack by TAMs, which can be visualized through various imaging assays in situ. The study sheds light on the underlying mechanism of biofilm-mediated inflammation on tumor progression and provides new insights into combined anti-biofilm therapy and immunotherapy strategies in clinical trials.
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Affiliation(s)
- Yanlin Deng
- Department of Biomedical Engineering, City University of Hong Kong, Kowloon, 999077, Hong Kong
| | - Yatian Fu
- Department of Biomedical Engineering, City University of Hong Kong, Kowloon, 999077, Hong Kong
- Hong Kong Center for Cerebro-Cardiovascular Health Engineering (COCHE), Kowloon, 999077, Hong Kong
| | - Song Lin Chua
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, Kowloon, 999077, China
- State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong SAR, Kowloon, 999077, China
- Shenzhen Key Laboratory of Food Biological Safety Control, Kowloon, 999077, Hong Kong
- Research Centre for Deep Space Explorations (RCDSE), The Hong Kong Polytechnic University, Hong Kong SAR, Kowloon, 999077, China
| | - Bee Luan Khoo
- Department of Biomedical Engineering, City University of Hong Kong, Kowloon, 999077, Hong Kong
- Hong Kong Center for Cerebro-Cardiovascular Health Engineering (COCHE), Kowloon, 999077, Hong Kong
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen-Futian Research Institute, Shenzhen, 518057, China
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24
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Shen Y, Chen JX, Li M, Xiang Z, Wu J, Wang YJ. Role of tumor-associated macrophages in common digestive system malignant tumors. World J Gastrointest Oncol 2023; 15:596-616. [PMID: 37123058 PMCID: PMC10134211 DOI: 10.4251/wjgo.v15.i4.596] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 02/12/2023] [Accepted: 03/30/2023] [Indexed: 04/12/2023] Open
Abstract
Many digestive system malignant tumors are characterized by high incidence and mortality rate. Increasing evidence has revealed that the tumor microenvironment (TME) is involved in cancer initiation and tumor progression. Tumor-associated macrophages (TAMs) are a predominant constituent of the TME, and participate in the regulation of various biological behaviors and influence the prognosis of digestive system cancer. TAMs can be mainly classified into the antitumor M1 phenotype and protumor M2 phenotype. The latter especially are crucial drivers of tumor invasion, growth, angiogenesis, metastasis, immunosuppression, and resistance to therapy. TAMs are of importance in the occurrence, development, diagnosis, prognosis, and treatment of common digestive system malignant tumors. In this review, we summarize the role of TAMs in common digestive system malignant tumors, including esophageal, gastric, colorectal, pancreatic and liver cancers. How TAMs promote the development of tumors, and how they act as potential therapeutic targets and their clinical applications are also described.
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Affiliation(s)
- Yue Shen
- Department of Dermatology, Suzhou Municipal Hospital, Suzhou 215008, Jiangsu Province, China
| | - Jia-Xi Chen
- School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Ming Li
- Department of Pathology, Suzhou Municipal Hospital, Suzhou 215008, Jiangsu Province, China
| | - Ze Xiang
- School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Jian Wu
- Department of Clinical Laboratory, Suzhou Municipal Hospital, Suzhou 215008, Jiangsu Province, China
| | - Yi-Jin Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong Province, China
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25
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Li Z, Qi J, Guo T, Li J. Research progress of Astragalus membranaceus in treating peritoneal metastatic cancer. JOURNAL OF ETHNOPHARMACOLOGY 2023; 305:116086. [PMID: 36587879 DOI: 10.1016/j.jep.2022.116086] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Peritoneal metastasis is a manifestation of advanced cancer often associated with a poor prognosis and poor response to treatment. Astragalus membranaceus (Fisch.) Bunge is a commonly used medicinal material in traditional Chinese medicine with various biological activities. In patients with cancer, Astragalus membranaceus has demonstrated anti-tumor effects, immune regulation, postoperative recurrence and metastasis prevention, and survival prolongation. AIM OF THE STUDY Peritoneal metastasis results from tumor cell and peritoneal microenvironment co-evolution. We aimed to introduce and discuss the specific mechanism of action of Astragalus membranaceus in peritoneal metastasis treatment to provide a new perspective for treatment and further research. MATERIALS AND METHODS We consulted reports on the anti-peritoneal metastases effects of Astragalus membranaceus from PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang databases, as well as Google Scholar. Meanwhile, we also obtained data from published medical works and doctoral and master's theses. Then, we focused on the research progress of Astragalus membranaceus in peritoneal metastatic cancer treatment. Plant names are provided in accordance with "The Plant List" (www.theplantlist.org). RESULTS To date, more than 200 compounds have been isolated from Astragalus membranaceus. Among them, Astragalus polysaccharides, saponins, and flavonoids are the main bioactive components, and their effects on cancer have been extensively studied. In this review, we systematically summarize the effects of Astragalus membranaceus on the peritoneal metastasis microenvironment and related mechanisms, including maintaining the integrity of peritoneal mesothelial cells, restoring the peritoneal immune microenvironment, and inhibiting the formation of tumor blood vessels, matrix metalloproteinase, and dense tumor spheroids. CONCLUSIONS Our analysis demonstrates that Astragalus membranaceus could be a potential therapeutic for preventing the occurrence of peritoneal metastasis. However, it might be too early to recommend its use owing to the paucity of reliable in vivo experiment, clinical data, and evidence of clinical efficacy. In addition, previous studies of Astragalus membranaceus report inconsistent and contradictory findings. Therefore, detailed in vitro, in vivo, and clinical studies on the mechanism of Astragalus membranaceus in peritoneal metastatic cancer treatment are warranted.
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Affiliation(s)
- Zhiyuan Li
- The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou, 730030, China
| | - Jinfeng Qi
- The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou, 730030, China
| | - Tiankang Guo
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, 730030, China
| | - Junliang Li
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou, 730030, China; The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou, 730030, China; The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730030, China.
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26
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Pharmacokinetic evaluation of poorly soluble compounds formulated as nano- or microcrystals after intraperitoneal injection to mice. Int J Pharm 2023; 636:122787. [PMID: 36894042 DOI: 10.1016/j.ijpharm.2023.122787] [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: 11/08/2022] [Revised: 02/21/2023] [Accepted: 02/24/2023] [Indexed: 03/09/2023]
Abstract
Intraperitonial (i.p.) delivery during initial stages of drug discovery can allow efficacy readouts for compounds which have suboptimal pharmacokinetics (PK) due to poor physiochemical properties and/or oral bioavailability. A major limitation for widespread use of i.p. administration is the paucity of published data and unclear mechanisms of absorption, particularly when using complex formulations. The aim of the present study was to investigate the PK of poorly soluble compounds with low oral bioavailability when administered i.p. as crystalline nano- and microsuspensions. Three compounds, with varying aqueous solubility (2, 7, and 38 µM, at 37 °C), were dosed to mice at 10 and 50 mg/kg. In vitro dissolution confirmed that nanocrystals dissolved faster than microcrystals and hence were expected to result in higher exposure after i.p. dosing. Surprisingly, the increase in dissolution rate with decrease in particle size did not result in higher in vivo exposure. In contrast, the microcrystals showed higher exposure. The potential of smaller particles to promote access to the lymphatic system is hypothesized and discussed as one plausible explanation. The present work demonstrates the importance of understanding physicochemical properties of drug formulations in the context of the microphysiology at the delivery site and how that knowledge can be leveraged to alter systemic PK.
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27
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Zhuang Y, Lan S, Zhong W, Huang F, Peng J, Zhang S. Comprehensive Analysis of PPMs in Pancreatic Adenocarcinoma Indicates the Value of PPM1K in the Tumor Microenvironment. Cancers (Basel) 2023; 15:cancers15020474. [PMID: 36672423 PMCID: PMC9856814 DOI: 10.3390/cancers15020474] [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: 09/10/2022] [Revised: 12/28/2022] [Accepted: 01/04/2023] [Indexed: 01/15/2023] Open
Abstract
Early metastasis and resistance to traditional therapy are responsible for the poor prognosis of pancreatic adenocarcinoma patients. Metal-dependent protein phosphatases (PPMs) have been proven to play a crucial role in the initiation and progression of various tumors. Nevertheless, the expression and function of distinct PPMs in pancreatic adenocarcinoma have not been fully elucidated. In this study, we investigated the mRNA expression level, prognostic value, and the relationship between the expression of PPMs and the tumor microenvironment in pancreatic adenocarcinoma using Oncomine, TCGA and GTEx, GEO, Kaplan-Meier plotter, STRING, GeneMANIA, and HPA databases and R packages. GO and KEGG analysis revealed that PPMs and their differential co-expression genes are attributed to cell-cell adhesion and immune cell infiltration. Among these, PPM1K was downregulated in the tissue and peripheral blood of PAAD patients, whose expression level was negatively related to poor prognosis. Further to this, PPM1K was found to play a role in the epithelial-mesenchymal transition and immune infiltration. ROC curves showed that PPM1K had a good predictive value for pancreatic adenocarcinoma. The knockdown of PPM1K markedly promoted the proliferation and migration of pancreatic cancer cells, confirming its role in tumor suppressor activity in PAAD. This study demonstrates the potential clinical utility of PPM1K in tumor immunotherapy and brings about novel insights into the prognostic value of PPM1K in pancreatic adenocarcinoma.
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Affiliation(s)
- Yanyan Zhuang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yanjiangxi Road, Guangzhou 510120, China
| | - Sihua Lan
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yanjiangxi Road, Guangzhou 510120, China
| | - Wa Zhong
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yanjiangxi Road, Guangzhou 510120, China
| | - Fengting Huang
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yanjiangxi Road, Guangzhou 510120, China
| | - Juanfei Peng
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yanjiangxi Road, Guangzhou 510120, China
| | - Shineng Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107, Yanjiangxi Road, Guangzhou 510120, China
- Correspondence:
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28
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Tumor immunology. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00003-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Anti-Inflammatory Mechanisms of Dietary Flavones: Tapping into Nature to Control Chronic Inflammation in Obesity and Cancer. Int J Mol Sci 2022; 23:ijms232415753. [PMID: 36555392 PMCID: PMC9779861 DOI: 10.3390/ijms232415753] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/07/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Flavones are natural phytochemicals broadly distributed in our diet. Their anti-inflammatory properties provide unique opportunities to control the innate immune system and inflammation. Here, we review the role of flavones in chronic inflammation with an emphasis on their impact on the molecular mechanisms underlying inflammatory diseases including obesity and cancer. Flavones can influence the innate immune cell repertoire restoring the immune landscape. Flavones impinge on NF-κB, STAT, COX-2, or NLRP3 inflammasome pathways reestablishing immune homeostasis. Devoid of adverse side effects, flavones could present alternative opportunities for the treatment and prevention of chronic inflammation that contributes to obesity and cancer.
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30
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Lee CW, Kuo CC, Liang CJ, Pan HJ, Shen CN, Lee CH. Effects of the media conditioned by various macrophage subtypes derived from THP-1 cells on tunneling nanotube formation in pancreatic cancer cells. BMC Mol Cell Biol 2022; 23:26. [PMID: 35794526 PMCID: PMC9258106 DOI: 10.1186/s12860-022-00428-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 06/30/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Tunneling nanotubes (TNTs) are special membrane structures for intercellular communications. Vital cargoes (such as mitochondria) could be delivered from healthy cells to rescue damaged ones through TNTs. The TNTs could be utilized for the purpose of systematic delivery of therapeutic agents between cells. However, there are insufficient studies on the controlled enhancement of TNT formations. The purpose of this study is to understand how macrophages influence the TNT formation in cancer cells.
Results
Here we compared the capabilities of inducing TNTs in human pancreatic cancer cells (PANC-1) of the media conditioned by M0, M1 and M2 macrophages derived from THP-1 cells. The M0 and M1 macrophage conditioned media promoted TNT formation. Using a focused ion beam to cut through a TNT, we observed tunnel-like structures inside dense cytoskeletons with scanning electron microscopy. The TNT formation correlated with raised motility, invasion, and epithelial–mesenchymal transition in the PANC-1 cells. Mitochondria and lysosomes were also found to be transported in the TNTs.
Conclusions
These results suggest that TNT formation could be one of the responses to the immune stress in pancreatic cancer cells caused by M0 and M1 macrophages. This finding is valuable for the development of macrophage-targeting cancer therapy.
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Minz AP, Das B, Mohapatra D, Suresh V, Mishra S, Senapati S. Gemcitabine induces polarization of mouse peritoneal macrophages towards M1-like and confers antitumor property by inducing ROS production. Clin Exp Metastasis 2022; 39:783-800. [PMID: 35838814 DOI: 10.1007/s10585-022-10178-3] [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: 01/27/2022] [Accepted: 06/27/2022] [Indexed: 11/03/2022]
Abstract
In patients with pancreatic cancer (PC), the peritoneal cavity is the second-most common site of metastasis after the liver. Peritoneal macrophages (PMs) have been demonstrated to play a significant role in the peritoneal metastases of different cancers. Gemcitabine (GEM) is known to affect PC-associated immune cells, including macrophages. However, its effect on PMs and its possible clinical implication is yet to be investigated. In this study, mouse-derived PMs were treated with GEM ex vivo to analyze the polarization status. Production of GEM-induced reactive oxygen species (ROS) and reactive nitrogen species was evaluated using DCFH-DA, DAF-FM, and Griess assay. Antitumor effects of PMs on UN-KC-6141and UN-KPC-961 murine PC cells were evaluated in presence and absence of GEM in vitro. Similarly, effect of GEM on human THP-1 macrophage polarization and its tumoricidal effect was studied in vitro. Furthermore, the effect of GEM-treated PMs on peritoneal metastasis of UN-KC-6141 cells was evaluated in a syngeneic mouse model of PC. GEM upregulated M1 phenotype-associated molecular markers (Tnf-α and Inos) in vitro in PMs obtained from naïve mouse. Moreover, IL-4-induced M2-like PMs reverted to M1-like after GEM treatment. Co-culture of UN-KC-6141 and UN-KPC-961 cancer cells with PMs in the presence of GEM increased apoptosis of these cells, whereas cell death was markedly reduced after N-acetyl-L-cysteine treatment. Corroborating these findings co-culture of GEM-treated human THP-1 macrophages also induced cell death in MIAPaCa-2 cancer cells. GEM-treated PMs injected intraperitoneally along with UN-KC-6141 cells into mice extended survival period, but did not stop disease progression and mortality. Together, GEM induced M1-like polarization of PMs from naive and/or M2-polarized PMs in a ROS-dependent manner. GEM-induced M1-like PMs prompted cytotoxicity in PC cells and delayed disease progression in vivo.
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Affiliation(s)
- Aliva Prity Minz
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, 751023, India.,Regional Centre for Biotechnology, Faridabad, Haryana, India
| | - Biswajit Das
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, 751023, India.,Department of Medical Biochemistry and Biophysics, Umea University, Umea, Sweden
| | - Debasish Mohapatra
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, 751023, India.,School of Biotechnology, KIIT University, Bhubaneswar, Odisha, India
| | - Voddu Suresh
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, 751023, India.,Regional Centre for Biotechnology, Faridabad, Haryana, India
| | - Swayambara Mishra
- Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, 751023, India.,Regional Centre for Biotechnology, Faridabad, Haryana, India
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Simón L, Sanhueza S, Gaete-Ramírez B, Varas-Godoy M, Quest AFG. Role of the Pro-Inflammatory Tumor Microenvironment in Extracellular Vesicle-Mediated Transfer of Therapy Resistance. Front Oncol 2022; 12:897205. [PMID: 35646668 PMCID: PMC9130576 DOI: 10.3389/fonc.2022.897205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 04/08/2022] [Indexed: 12/03/2022] Open
Abstract
Advances in our understanding of cancer biology have contributed to generating different treatments to improve the survival of cancer patients. However, although initially most of the therapies are effective, relapse and recurrence occur in a large percentage of these cases after the treatment, and patients then die subsequently due to the development of therapy resistance in residual cancer cells. A large spectrum of molecular and cellular mechanisms have been identified as important contributors to therapy resistance, and more recently the inflammatory tumor microenvironment (TME) has been ascribed an important function as a source of signals generated by the TME that modulate cellular processes in the tumor cells, such as to favor the acquisition of therapy resistance. Currently, extracellular vesicles (EVs) are considered one of the main means of communication between cells of the TME and have emerged as crucial modulators of cancer drug resistance. Important in this context is, also, the inflammatory TME that can be caused by several conditions, including hypoxia and following chemotherapy, among others. These inflammatory conditions modulate the release and composition of EVs within the TME, which in turn alters the responses of the tumor cells to cancer therapies. The TME has been ascribed an important function as a source of signals that modulate cellular processes in the tumor cells, such as to favor the acquisition of therapy resistance. Although generally the main cellular components considered to participate in generating a pro-inflammatory TME are from the immune system (for instance, macrophages), more recently other types of cells of the TME have also been shown to participate in this process, including adipocytes, cancer-associated fibroblasts, endothelial cells, cancer stem cells, as well as the tumor cells. In this review, we focus on summarizing available information relating to the impact of a pro-inflammatory tumor microenvironment on the release of EVs derived from both cancer cells and cells of the TME, and how these EVs contribute to resistance to cancer therapies.
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Affiliation(s)
- Layla Simón
- Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Escuela de Nutrición y Dietética, Universidad Finis Terrae, Santiago, Chile
| | - Sofía Sanhueza
- Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Belén Gaete-Ramírez
- Cancer Cell Biology Laboratory, Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Manuel Varas-Godoy
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Cancer Cell Biology Laboratory, Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile.,Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago, Chile
| | - Andrew F G Quest
- Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile.,Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile
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Early Steps of Resistance to Targeted Therapies in Non-Small-Cell Lung Cancer. Cancers (Basel) 2022; 14:cancers14112613. [PMID: 35681591 PMCID: PMC9179469 DOI: 10.3390/cancers14112613] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/19/2022] [Accepted: 05/19/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Patients with lung cancer benefit from more effective treatments, such as targeted therapies, and the overall survival has increased in the past decade. However, the efficacy of targeted therapies is limited due to the emergence of resistance. Growing evidence suggests that resistances may arise from a small population of drug-tolerant persister (DTP) cells. Understanding the mechanisms underlying DTP survival is therefore crucial to develop therapeutic strategies to prevent the development of resistance. Herein, we propose an overview of the current scientific knowledge about the characterisation of DTP, and summarise the new therapeutic strategies that are tested to target these cells. Abstract Lung cancer is the leading cause of cancer-related deaths among men and women worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective therapies for advanced non-small-cell lung cancer (NSCLC) patients harbouring EGFR-activating mutations, but are not curative due to the inevitable emergence of resistances. Recent in vitro studies suggest that resistance to EGFR-TKI may arise from a small population of drug-tolerant persister cells (DTP) through non-genetic reprogramming, by entering a reversible slow-to-non-proliferative state, before developing genetically derived resistances. Deciphering the molecular mechanisms governing the dynamics of the drug-tolerant state is therefore a priority to provide sustainable therapeutic solutions for patients. An increasing number of molecular mechanisms underlying DTP survival are being described, such as chromatin and epigenetic remodelling, the reactivation of anti-apoptotic/survival pathways, metabolic reprogramming, and interactions with their micro-environment. Here, we review and discuss the existing proposed mechanisms involved in the DTP state. We describe their biological features, molecular mechanisms of tolerance, and the therapeutic strategies that are tested to target the DTP.
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Yan D, Zhao Q, Du Z, Li H, Geng R, Yang W, Zhang X, Cao J, Yi N, Zhou J, Tang Z. Development and validation of an immune-related gene signature for predicting the radiosensitivity of lower-grade gliomas. Sci Rep 2022; 12:6698. [PMID: 35461367 PMCID: PMC9035187 DOI: 10.1038/s41598-022-10601-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 03/22/2022] [Indexed: 12/21/2022] Open
Abstract
Radiotherapy is an important treatment modality for lower-grade gliomas (LGGs) patients. This analysis was conducted to develop an immune-related radiosensitivity gene signature to predict the survival of LGGs patients who received radiotherapy. The clinical and RNA sequencing data of LGGs were obtained from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). Lasso regression analyses were used to construct a 21-gene signature to identify the LGGs patients who could benefit from radiotherapy. Based on this radiosensitivity signature, patients were classified into a radiosensitive (RS) group and a radioresistant (RR) group. According to the Kaplan–Meier analysis results of the TCGA dataset and the two CGGA validation datasets, the RS group had a higher overall survival rate than that of the RR group. This gene signature was RT-specific and an independent prognostic indicator. The nomogram model performed well in predicting 3-, and 5-year survival of LGGs patients after radiotherapy by this gene signature and other clinical factors (age, sex, grade, IDH mutations, 1p/19q codeletion). In summary, this signature is a powerful supplement to the prognostic factors of LGGs patients with radiotherapy and may provide an opportunity to incorporate individual tumor biology into clinical decision making in radiation oncology.
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35
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Hama S, Nishi T, Isono E, Itakura S, Yoshikawa Y, Nishimoto A, Suzuki S, Kirimura N, Todo H, Kogure K. Intraperitoneal administration of nanoparticles containing tocopheryl succinate prevents peritoneal dissemination. Cancer Sci 2022; 113:1779-1788. [PMID: 35253340 PMCID: PMC9128176 DOI: 10.1111/cas.15321] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 03/02/2022] [Accepted: 03/03/2022] [Indexed: 11/30/2022] Open
Abstract
Intraperitoneal administration of anticancer nanoparticles is a rational strategy for preventing peritoneal dissemination of colon cancer owing to the prolonged retention of nanoparticles in the abdominal cavity. However, instability of nanoparticles in body fluids causes inefficient retention, reducing its anticancer effects. We have previously developed anticancer nanoparticles containing tocopheryl succinate, which showed high in vivo stability and multifunctional anticancer effects. In the present study, we have demonstrated that peritoneal dissemination derived from colon cancer was prevented by intraperitoneal administration of tocopheryl succinate nanoparticles. The biodistribution of tocopheryl succinate nanoparticles was evaluated by inductively coupled plasma mass spectroscopy and imaging analysis in mice administered quantum dot encapsulated tocopheryl succinate nanoparticles. Intraperitoneal administration of tocopheryl succinate nanoparticles showed longer retention in the abdominal cavity than by its intravenous administration. Moreover, due to effective biodistribution, tumor growth was prevented by intraperitoneal administration of tocopheryl succinate nanoparticles. Furthermore, the anticancer effect was attributed to the inhibition of cancer cell proliferation and improvement of the intraperitoneal microenvironment, such as decrease in the levels of vascular endothelial growth factor A, interleukin 10, and M2-like phenotype of tumor-associated macrophages. Collectively, intraperitoneal administration of tocopheryl succinate nanoparticles is expected to have multifaceted antitumor effects against colon cancer with peritoneal dissemination.
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Affiliation(s)
- Susumu Hama
- Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Tokyo, 202-8585, Japan
| | - Takayuki Nishi
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan
| | - Eitaro Isono
- Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Tokyo, 202-8585, Japan
| | - Shoko Itakura
- Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama, 350-0295, Japan
| | - Yutaka Yoshikawa
- Department of Health, Sports, and Nutrition, Faculty of Health and Welfare, Kobe Women's University, Kobe, 650-0046, Japan
| | - Akinori Nishimoto
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan
| | - Satoko Suzuki
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan
| | - Naoko Kirimura
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto, 607-8414, Japan
| | - Hiroaki Todo
- Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama, 350-0295, Japan
| | - Kentaro Kogure
- Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8505, Japan
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Tretyakova MS, Subbalakshmi AR, Menyailo ME, Jolly MK, Denisov EV. Tumor Hybrid Cells: Nature and Biological Significance. Front Cell Dev Biol 2022; 10:814714. [PMID: 35242760 PMCID: PMC8886020 DOI: 10.3389/fcell.2022.814714] [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: 11/14/2021] [Accepted: 01/25/2022] [Indexed: 11/13/2022] Open
Abstract
Metastasis is the leading cause of cancer death and can be realized through the phenomenon of tumor cell fusion. The fusion of tumor cells with other tumor or normal cells leads to the appearance of tumor hybrid cells (THCs) exhibiting novel properties such as increased proliferation and migration, drug resistance, decreased apoptosis rate, and avoiding immune surveillance. Experimental studies showed the association of THCs with a high frequency of cancer metastasis; however, the underlying mechanisms remain unclear. Many other questions also remain to be answered: the role of genetic alterations in tumor cell fusion, the molecular landscape of cells after fusion, the lifetime and fate of different THCs, and the specific markers of THCs, and their correlation with various cancers and clinicopathological parameters. In this review, we discuss the factors and potential mechanisms involved in the occurrence of THCs, the types of THCs, and their role in cancer drug resistance and metastasis, as well as potential therapeutic approaches for the prevention, and targeting of tumor cell fusion. In conclusion, we emphasize the current knowledge gaps in the biology of THCs that should be addressed to develop highly effective therapeutics and strategies for metastasis suppression.
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Affiliation(s)
- Maria S Tretyakova
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Ayalur R Subbalakshmi
- Cancer Systems Biology Laboratory, Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India
| | - Maxim E Menyailo
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Mohit Kumar Jolly
- Cancer Systems Biology Laboratory, Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India
| | - Evgeny V Denisov
- Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
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Hammel JH, Zatorski JM, Cook SR, Pompano RR, Munson JM. Engineering in vitro immune-competent tissue models for testing and evaluation of therapeutics. Adv Drug Deliv Rev 2022; 182:114111. [PMID: 35031388 PMCID: PMC8908413 DOI: 10.1016/j.addr.2022.114111] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 11/16/2021] [Accepted: 01/07/2022] [Indexed: 12/13/2022]
Abstract
Advances in 3D cell culture, microscale fluidic control, and cellular analysis have enabled the development of more physiologically-relevant engineered models of human organs with precise control of the cellular microenvironment. Engineered models have been used successfully to answer fundamental biological questions and to screen therapeutics, but these often neglect key elements of the immune system. There are immune elements in every tissue that contribute to healthy and diseased states. Including immune function will be essential for effective preclinical testing of therapeutics for inflammatory and immune-modulated diseases. In this review, we first discuss the key components to consider in designing engineered immune-competent models in terms of physical, chemical, and biological cues. Next, we review recent applications of models of immunity for screening therapeutics for cancer, preclinical evaluation of engineered T cells, modeling autoimmunity, and screening vaccine efficacy. Future work is needed to further recapitulate immune responses in engineered models for the most informative therapeutic screening and evaluation.
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Affiliation(s)
- Jennifer H. Hammel
- Fralin Biomedical Research Institute and Department of Biomedical Engineering and Mechanics, Virginia Tech, Roanoke, Virginia 24016, USA
| | - Jonathan M. Zatorski
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, USA
| | - Sophie R. Cook
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, USA
| | - Rebecca R. Pompano
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, USA,Department of Biomedical Engineering, University of Virginia; Charlottesville, Virginia 22904, USA,Carter Immunology Center and UVA Cancer Center, University of Virginia School of Medicine, Charlottesville, Virginia 22903
| | - Jennifer M. Munson
- Fralin Biomedical Research Institute and Department of Biomedical Engineering and Mechanics, Virginia Tech, Roanoke, Virginia 24016, USA
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Tumor-associated macrophages in cancer: recent advancements in cancer nanoimmunotherapies. J Exp Clin Cancer Res 2022; 41:68. [PMID: 35183252 PMCID: PMC8857848 DOI: 10.1186/s13046-022-02272-x] [Citation(s) in RCA: 184] [Impact Index Per Article: 61.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/22/2022] [Indexed: 12/21/2022] Open
Abstract
AbstractCancer immunotherapy has emerged as a novel cancer treatment, although recent immunotherapy trials have produced suboptimal outcomes, with durable responses seen only in a small number of patients. The tumor microenvironment (TME) has been shown to be responsible for tumor immune escape and therapy failure. The vital component of the TME is tumor-associated macrophages (TAMs), which are usually associated with poor prognosis and drug resistance, including immunotherapies, and have emerged as promising targets for cancer immunotherapy. Recently, nanoparticles, because of their unique physicochemical characteristics, have emerged as crucial translational moieties in tackling tumor-promoting TAMs that amplify immune responses and sensitize tumors to immunotherapies in a safe and effective manner. In this review, we mainly described the current potential nanomaterial-based therapeutic strategies that target TAMs, including restricting TAMs survival, inhibiting TAMs recruitment to tumors and functionally repolarizing tumor-supportive TAMs to antitumor type. The current understanding of the origin and polarization of TAMs, their crucial role in cancer progression and prognostic significance was also discussed in this review. We also highlighted the recent evolution of chimeric antigen receptor (CAR)-macrophage cell therapy.
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Quan Q, Wu J, Yu M, Tang J. Immune micro-environment and drug analysis of peritoneal endometriosis based on epithelial-mesenchymal transition classification. Front Endocrinol (Lausanne) 2022; 13:1035158. [PMID: 36523599 PMCID: PMC9745086 DOI: 10.3389/fendo.2022.1035158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/15/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Epithelial-mesenchymal transition (EMT) is a complex event that drives polar epithelial cells transform from adherent cells to motile mesenchymal cells, in which are involved immune cells and stroma cells. EMT plays crucial roles in migration and invasion of endometriosis. The interaction of endometrial implants with the surrounding peritoneal micro-environment probably affects the development of peritoneal endometriosis. To date, very few studies have been carried out on peritoneal endometriosis sub-type classification and micro-environment analysis based on EMT. The purpose of this study is to investigate the potential application of EMT-based classification in precise diagnosis and treatment of peritoneal endometriosis. METHOD Based on EMT hallmark genes, 76 peritoneal endometriosis samples were classified into two clusters by consistent cluster classification. EMT scores, which calculated by Z score of 8 epithelial cell marker genes and 8 mesenchymal cell marker genes, were compared in two clusters. Then, immune scores and the abundances of corresponding immune cells, stroma scores and the abundances of corresponding stroma cells were analyzed by the "xCell" package. Futhermore, a diagnostic model was constructed based on 9 diagnostic markers which related to immune score and stroma score by Lasso-Logistic regression analysis. Finally, based on EMT classification, a total of 8 targeted drugs against two clusters were screened out by drug susceptibility analysis via "pRRophetic" package. RESULTS Hallmark epithelial-mesenchymal transition was the mainly enriched pathway of differentially expressed genes between peritoneal endometriosis tissues and endometrium tissues. Compared with cluster 2, EMT score and the abundances of most infiltrating stroma cell were significantly higher, while the abundances of most infiltrating immune cells were dramatically less. The diagnostic model could accurately distinguish cluster 1 from cluster 2. Pathway analysis showed drug candidates targeting cluster 1 mainly act on the IGF-1 signaling pathway, and drug candidates targeting cluster 2 mainly block the EGFR signaling pathway. CONCLUSION In peritoneal endometriosis, EMT was probably promoted by stroma cell infiltration and inhibited by immune cell infiltration. Besides, our study highlighted the potential uses of the EMT classification in the precise diagnosis and treatment of peritoneal endometriosis.
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Affiliation(s)
- Qingli Quan
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, China
- *Correspondence: Qingli Quan, ; Jia Tang,
| | - Jiabao Wu
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, China
| | - Meixing Yu
- Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Jia Tang
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute (Guangdong Provincial Fertility Hospital), Guangzhou, China
- *Correspondence: Qingli Quan, ; Jia Tang,
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40
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Alphavirus-Driven Interferon Gamma (IFNg) Expression Inhibits Tumor Growth in Orthotopic 4T1 Breast Cancer Model. Vaccines (Basel) 2021; 9:vaccines9111247. [PMID: 34835178 PMCID: PMC8620866 DOI: 10.3390/vaccines9111247] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 09/10/2021] [Accepted: 10/18/2021] [Indexed: 12/13/2022] Open
Abstract
Interferon gamma (IFNg) is a pleiotropic cytokine that can potentially reprogram the tumor microenvironment; however, the antitumor immunomodulatory properties of IFNg still need to be validated due to variable therapeutic outcomes in preclinical and clinical studies. We developed a replication-deficient Semliki Forest virus vector expressing IFNg (SFV/IFNg) and evaluated its immunomodulatory antitumor potential in vitro in a model of 3D spheroids and in vivo in an immunocompetent 4T1 mouse breast cancer model. We demonstrated that SFV-derived, IFN-g-stimulated bone marrow macrophages can be used to acquire the tumoricidal M1 phenotype in 3D nonattached conditions. Coculturing SFV/IFNg-infected 4T1 spheroids with BMDMs inhibited spheroid growth. In the orthotopic 4T1 mouse model, intratumoral administration of SFV/IFNg virus particles alone or in combination with the Pam3CSK4 TLR2/1 ligand led to significant inhibition of tumor growth compared to the administration of the control SFV/Luc virus particles. Analysis of the composition of intratumoral lymphoid cells isolated from tumors after SFV/IFNg treatment revealed increased CD4+ and CD8+ and decreased T-reg (CD4+/CD25+/FoxP3+) cell populations. Furthermore, a significant decrease in the populations of cells bearing myeloid cell markers CD11b, CD38, and CD206 was observed. In conclusion, the SFV/IFNg vector induces a therapeutic antitumor T-cell response and inhibits myeloid cell infiltration in treated tumors.
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41
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Wu T, Tang C, Tao R, Yong X, Jiang Q, Feng C. PD-L1-Mediated Immunosuppression in Oral Squamous Cell Carcinoma: Relationship With Macrophage Infiltration and Epithelial to Mesenchymal Transition Markers. Front Immunol 2021; 12:693881. [PMID: 34552581 PMCID: PMC8450501 DOI: 10.3389/fimmu.2021.693881] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 08/12/2021] [Indexed: 12/29/2022] Open
Abstract
To date, immune check-point inhibitors (ICIs), particularly inhibitors of programmed cell death-1 (PD-1) and PD ligand-1 (PD-L1) have become prominent in cancer treatment and also improved life expectancy of cancer patients. As key regulators of PD-1/PD-L1 axis, the recruitment of tumor-associated macrophages (TAMs) enhances aggressive and invasive properties of tumors in immunosuppressive tumor microenvironment (TME) and promotes epithelial-mesenchymal transition (EMT). The aims of the study were first to characterize the critical links among PD-L1, TME and EMT process and, further, to explore the sensitivity of different chemical agents to different PD-L1 expression groups. Bioinformatical analysis revealed that PD-L1 was highly expressed in OSCC and higher PD-L1 expression correlated with worse survival in patients. Notably, PD-L1 was positively correlated with macrophages infiltration and EMT markers gene expression. Moreover, patients in the PD-L1high group were at a significant chance of benefiting from ICI treatment and they also showed higher sensitivity to the chemical drugs (olaparib, paclitaxel, docetaxel, and pazopanib). These findings implicate PD-L1 could serve as a novel target for prognostic and therapeutic approaches in OSCC patients; PD-L1-mediated immune evasion might be attributable to the infiltration of macrophages, resulting EMT progress; Chemical agents in combination with PD-L1 inhibitor could be served as personalized treatment plan for OSCC patients so as to maximize patient benefit.
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Affiliation(s)
- Tiantian Wu
- Department of Periodontics and Oral Medicine, College of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Universities and Colleges Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, China.,Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Medical University, Nanning, China
| | - Caijin Tang
- Department of Periodontics and Oral Medicine, College of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Universities and Colleges Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, China.,Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Medical University, Nanning, China
| | - Renchuan Tao
- Department of Periodontics and Oral Medicine, College of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Universities and Colleges Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, China.,Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Medical University, Nanning, China
| | - Xiangzhi Yong
- Department of Periodontics and Oral Medicine, College of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Universities and Colleges Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, China
| | - Qiaozhi Jiang
- Department of Periodontics and Oral Medicine, College of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Universities and Colleges Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, China.,Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Medical University, Nanning, China
| | - Cong Feng
- Department of Periodontics and Oral Medicine, College of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Health Commission Key Laboratory of Prevention and Treatment for Oral Infectious Diseases, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Universities and Colleges Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, China.,Guangxi Key Laboratory of AIDS Prevention and Treatment, Guangxi Medical University, Nanning, China
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Poh AR, Ernst M. Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Therapeutic Opportunities and Clinical Challenges. Cancers (Basel) 2021; 13:cancers13122860. [PMID: 34201127 PMCID: PMC8226457 DOI: 10.3390/cancers13122860] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/03/2021] [Accepted: 06/06/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Macrophages are a major component of the pancreatic tumor microenvironment, and their increased abundance is associated with poor patient survival. Given the multi-faceted role of macrophages in promoting pancreatic tumor development and progression, these cells represent promising targets for anti-cancer therapy. Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of less than 10%. Macrophages are one of the earliest infiltrating cells in the pancreatic tumor microenvironment, and are associated with an increased risk of disease progression, recurrence, metastasis, and shorter overall survival. Pre-clinical studies have demonstrated an unequivocal role of macrophages in PDAC by contributing to chronic inflammation, cancer cell stemness, desmoplasia, immune suppression, angiogenesis, invasion, metastasis, and drug resistance. Several macrophage-targeting therapies have also been investigated in pre-clinical models, and include macrophage depletion, inhibiting macrophage recruitment, and macrophage reprogramming. However, the effectiveness of these drugs in pre-clinical models has not always translated into clinical trials. In this review, we discuss the molecular mechanisms that underpin macrophage heterogeneity within the pancreatic tumor microenvironment, and examine the contribution of macrophages at various stages of PDAC progression. We also provide a comprehensive update of macrophage-targeting therapies that are currently undergoing clinical evaluation, and discuss clinical challenges associated with these treatment modalities in human PDAC patients.
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Xie R, Ruan S, Liu J, Qin L, Yang C, Tong F, Lei T, Shevtsov M, Gao H, Qin Y. Furin-instructed aggregated gold nanoparticles for re-educating tumor associated macrophages and overcoming breast cancer chemoresistance. Biomaterials 2021; 275:120891. [PMID: 34051669 DOI: 10.1016/j.biomaterials.2021.120891] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 04/27/2021] [Accepted: 05/06/2021] [Indexed: 12/26/2022]
Abstract
Insufficient drug accumulation and chemoresistance remain two major challenges in cancer chemotherapy. Herein, we designed a furin-responsive aggregated nanoplatform loaded with doxorubicin (DOX) and hydroxychloroquine (HCQ) (AuNPs-D&H-R&C) to combine chemotherapy, autophagy inhibition and macrophage polarization. AuNPs-D&H-R&C could passively target breast tumor via enhanced permeability and retention (EPR) effect after systemic administration and further aggregate together triggered by furin overexpressed in breast cancer. The in situ aggregations hindered the back-flow of NPs to the bloodstream and exocytosis of tumor cells, leading to enhanced drug accumulation within tumors. Moreover, upon exposure to acidic pH in the endosomes/lysosomes, HCQ was efficiently released and it inhibited autophagy and thus restored the sensitivity of tumor cell to DOX. Meanwhile, autophagy inhibition could reprogram tumor-promoting M2-like TAMs to anti-tumor M1 phenotype, exerting a synergistic effect in overcoming chemoresistance. In vitro studies demonstrated the superiority of furin-triggered aggregated AuNPs delivery system in enhancing drug accumulation in breast tumor, compared with PEGlyated AuNPs. The co-delivery of DOX and HCQ showed much improved chemotherapeutic efficiency to chemoresistant MCF-7/ADR breast tumor, in large part due to macrophage polarization. In conclusion, we developed a stimulus-responsive delivery system and proposed a potential combination strategy to overcome chemoresistance in cancer chemotherapy.
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Affiliation(s)
- Rou Xie
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Shaobo Ruan
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Jiaqi Liu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Lin Qin
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Chuanyao Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Fan Tong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Ting Lei
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Maxim Shevtsov
- Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg, 194064, Russia
| | - Huile Gao
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China.
| | - Yi Qin
- Department of Orthopedics, Zhuhai Hospital, Jinan University, Zhuhai People's Hospital, 79 Kangning Road, Zhuhai, 519000, China.
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Ni Y, Zhou X, Yang J, Shi H, Li H, Zhao X, Ma X. The Role of Tumor-Stroma Interactions in Drug Resistance Within Tumor Microenvironment. Front Cell Dev Biol 2021; 9:637675. [PMID: 34095111 PMCID: PMC8173135 DOI: 10.3389/fcell.2021.637675] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 04/19/2021] [Indexed: 02/05/2023] Open
Abstract
Cancer cells resistance to various therapies remains to be a key challenge nowadays. For a long time, scientists focused on tumor cells themselves for the mechanisms of acquired drug resistance. However, recent evidence showed that tumor microenvironment (TME) is essential for regulating immune escape, drug resistance, progression and metastasis of malignant cells. Reciprocal interactions between cancer cells and non-malignant cells within this milieu often reshape the TME and promote drug resistance. Therefore, advanced knowledge about these sophisticated interactions is significant for the design of effective therapeutic approaches. In this review, we highlight cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), T-regulatory lymphocytes (Tregs), mesenchymal stem cells (MSCs), cancer-associated adipocytes (CAAs), and tumor endothelial cells (TECs) existing in TME, as well as their multiple cross-talk with tumor cells, which eventually endows tumor cells with therapeutic resistance.
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Affiliation(s)
- Yanghong Ni
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Xiaoting Zhou
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Jia Yang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Houhui Shi
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Hongyi Li
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Xia Zhao
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Xuelei Ma
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
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45
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Gao C, Quan MY, Chen QJ, Yang R, Wu Y, Liu JY, Lin ZY, Li X, Cai JT, Jiang TF, Xu L, Mossahebi-Mohammadi M, Guo Q, Zhang JS. Yap1-2 Isoform Is the Primary Mediator in TGF-β1 Induced EMT in Pancreatic Cancer. Front Oncol 2021; 11:649290. [PMID: 34094936 PMCID: PMC8170464 DOI: 10.3389/fonc.2021.649290] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 03/26/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive human malignancy and intrinsically resistant to conventional therapies. YAP1, as a key downstream effector of the Hippo pathway, plays an important role in tumorigenesis including PDAC. Alternative mRNA splicing of YAP1 results in at least 8 protein isoforms, which are divided into two subgroups (YAP1-1 and YAP1-2) based on the presence of either a single or double WW domains. We investigated the functions and regulatory mechanisms of YAP1-1 and YAP1-2 in PDAC cells induced by TGF-β to undergo epithelial-to-mesenchymal transition (EMT). CRISPR-Cas9 and shRNA were used to silence YAP1 expression in pancreatic cancer cells. Re-constituted lentivirus mediated overexpression of each single YAP1 isoform was generated in the parental knockout L3.6 cells. EMT was induced by treatment with TGF-β, EGF and bFGF in parental and the constructed stable cell lines. Western blot and qPCR were used to detect the expression of EMT markers. Scratch wound healing and transwell assays were used to detect cell migration. The stability and subcellular localization of YAP1 proteins were determined by Western blot analysis, immunofluorescence, as well as ubiquitination assays. We showed that TGF-β, EGF and bFGF all significantly promoted EMT in PDAC cells, which was inhibited by knockdown of YAP1 expression. Interestingly, YAP1-1 stable cells exhibited a stronger migratory ability than YAP1-2 cells under normal culture condition. However, upon TGF-β treatment, L3.6-YAP1-2 cells exhibited a stronger migratory ability than L3.6-YAP1-1 cells. Mechanistically, TGF-β treatment preferentially stabilizes YAP1-2 and enhances its nuclear localization. Furthermore, TGF-β-induced EMT and YAP1-2 activity were both blocked by inhibition of AKT signaling. Our results showed that both YAP1-1 and YAP1-2 isoforms are important mediators in the EMT process of pancreatic cancer. However, YAP1-2 is more important in mediating TGF-β-induced EMT, which requires AKT signaling.
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Affiliation(s)
- Chao Gao
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Mei-Yu Quan
- The Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qian-Jie Chen
- Department of Pharmacy, Cangnan Hospital Affiliated to Wenzhou Medical University, Wenzhou, China
| | - Ruo Yang
- International Collaborative Center on Growth Factor Research, and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yuanyuan Wu
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Jia-Yu Liu
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Zhong-Yuan Lin
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Xue Li
- International Collaborative Center on Growth Factor Research, and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Jue-Ting Cai
- International Collaborative Center on Growth Factor Research, and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | | | - Le Xu
- Division of Respiratory Medicine, Taizhou Enze Hospital, Taizhou, China
| | - Majid Mossahebi-Mohammadi
- International Collaborative Center on Growth Factor Research, and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qiang Guo
- International Collaborative Center on Growth Factor Research, and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Jin-San Zhang
- Institute of Life Sciences, Wenzhou University, Wenzhou, China.,International Collaborative Center on Growth Factor Research, and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
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46
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Kothari A, Flick MJ. Coagulation Signaling through PAR1 as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2021; 22:ijms22105138. [PMID: 34066284 PMCID: PMC8152032 DOI: 10.3390/ijms22105138] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/05/2021] [Accepted: 05/10/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with a 5-year survival rate of less than 10% following diagnosis. The aggressive and invasive properties of pancreatic cancer tumors coupled with poor diagnostic options contribute to the high mortality rate since most patients present with late-stage disease. Accordingly, PDAC is linked to the highest rate of cancer-associated venous thromboembolic disease of all solid tumor malignancies. However, in addition to promoting clot formation, recent studies suggest that the coagulation system in PDAC mediates a reciprocal relationship, whereby coagulation proteases and receptors promote PDAC tumor progression and dissemination. Here, upregulation of tissue factor (TF) by tumor cells can drive local generation of the central coagulation protease thrombin that promotes cell signaling activity through protease-activated receptors (PARs) expressed by both tumor cells and multiple stromal cell subsets. Moreover, the TF-thrombin-PAR1 signaling axis appears to be a major mechanism of cancer progression in general and PDAC in particular. Here, we summarize the current literature regarding the role of PAR1 in PDAC and review possibilities for pharmacologically targeting PAR1 as a PDAC therapeutic approach.
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47
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Sharma V, Aggarwal A, Jacob J, Sahni D. Myeloid-derived suppressor cells: Bridging the gap between inflammation and pancreatic adenocarcinoma. Scand J Immunol 2021; 93:e13021. [PMID: 33455004 DOI: 10.1111/sji.13021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 01/09/2021] [Accepted: 01/10/2021] [Indexed: 12/29/2022]
Abstract
Pancreatic cancer has been identified as one of the deadliest malignancies because it remains asymptomatic and usually presents in the advanced stage. Tumour immune evasion is a well-known mechanism of tumorigenesis in various forms of human malignancies. Chronic inflammation via complex networking of various inflammatory cytokines in the local tissue microenvironment dysregulates the immune system and support tumour development. Pro-inflammatory mediators present in the tumour microenvironment increase the tumour burden by causing immune suppression through the generation of myeloid-derived suppressor cells (MDSCs) and T regulatory cells. These cells, along-with myofibroblasts, create a highly immunosuppressive and resistant tumour microenvironment and are thus considered as one of the culprits for the failure of anti-cancer chemotherapies in pancreatic adenocarcinoma patients. Targeting these MDSCs using various combinatorial approaches might have the potential for abrogating the resistance and suppressive nature of the pancreatic tumour microenvironment. Therefore, there is more curiosity in studying the crosstalk of MDSCs with other immune cells during pathological conditions and the underlying mechanisms of immunosuppression in the current scenario. In this article, the possible role of MDSCs in inflammation-mediated tumour progression of pancreatic adenocarcinoma has been discussed.
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Affiliation(s)
- Vinit Sharma
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Anjali Aggarwal
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Justin Jacob
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Daisy Sahni
- Department of Anatomy, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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48
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Manna D, Sarkar D. Multifunctional Role of Astrocyte Elevated Gene-1 (AEG-1) in Cancer: Focus on Drug Resistance. Cancers (Basel) 2021; 13:cancers13081792. [PMID: 33918653 PMCID: PMC8069505 DOI: 10.3390/cancers13081792] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/31/2021] [Accepted: 04/04/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Chemotherapy is a major mode of treatment for cancers. However, cancer cells adapt to survive in stressful conditions and in many cases, they are inherently resistant to chemotherapy. Additionally, after initial response to chemotherapy, the surviving cancer cells acquire new alterations making them chemoresistant. Genes that help adapt the cancer cells to cope with stress often contribute to chemoresistance and one such gene is Astrocyte elevated gene-1 (AEG-1). AEG-1 levels are increased in all cancers studied to date and AEG-1 contributes to the development of highly aggressive, metastatic cancers. In this review, we provide a comprehensive description of the mechanism by which AEG-1 augments tumor development with special focus on its ability to regulate chemoresistance. We also discuss potential ways to inhibit AEG-1 to overcome chemoresistance. Abstract Cancer development results from the acquisition of numerous genetic and epigenetic alterations in cancer cells themselves, as well as continuous changes in their microenvironment. The plasticity of cancer cells allows them to continuously adapt to selective pressures brought forth by exogenous environmental stresses, the internal milieu of the tumor and cancer treatment itself. Resistance to treatment, either inherent or acquired after the commencement of treatment, is a major obstacle an oncologist confronts in an endeavor to efficiently manage the disease. Resistance to chemotherapy, chemoresistance, is an important hallmark of aggressive cancers, and driver oncogene-induced signaling pathways and molecular abnormalities create the platform for chemoresistance. The oncogene Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) is overexpressed in a diverse array of cancers, and its overexpression promotes all the hallmarks of cancer, such as proliferation, invasion, metastasis, angiogenesis and chemoresistance. The present review provides a comprehensive description of the molecular mechanism by which AEG-1 promotes tumorigenesis, with a special emphasis on its ability to regulate chemoresistance.
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49
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Duan Z, Luo Y. Targeting macrophages in cancer immunotherapy. Signal Transduct Target Ther 2021; 6:127. [PMID: 33767177 PMCID: PMC7994399 DOI: 10.1038/s41392-021-00506-6] [Citation(s) in RCA: 392] [Impact Index Per Article: 98.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 01/14/2021] [Accepted: 01/22/2021] [Indexed: 02/07/2023] Open
Abstract
Immunotherapy is regarded as the most promising treatment for cancers. Various cancer immunotherapies, including adoptive cellular immunotherapy, tumor vaccines, antibodies, immune checkpoint inhibitors, and small-molecule inhibitors, have achieved certain successes. In this review, we summarize the role of macrophages in current immunotherapies and the advantages of targeting macrophages. To better understand and make better use of this type of cell, their development and differentiation characteristics, categories, typical markers, and functions were collated at the beginning of the review. Therapeutic strategies based on or combined with macrophages have the potential to improve the treatment efficacy of cancer therapies.
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Affiliation(s)
- Zhaojun Duan
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, China
- Collaborative Innovation Center for Biotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yunping Luo
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, China.
- Collaborative Innovation Center for Biotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, China.
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50
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Carpenter E, Nelson S, Bednar F, Cho C, Nathan H, Sahai V, di Magliano MP, Frankel TL. Immunotherapy for pancreatic ductal adenocarcinoma. J Surg Oncol 2021; 123:751-759. [PMID: 33595893 DOI: 10.1002/jso.26312] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/05/2020] [Accepted: 11/06/2020] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal cancer with an urgent need for better medical therapies. Efforts have been made to investigate the efficacy of immunotherapy, particularly given the hallmarks of immune suppression and exhaustion in PDAC tumors. Here, we review the molecular components responsible for the immune-privileged state in PDAC and provide an overview of the immunotherapeutic strategies for PDAC including vaccine therapy, checkpoint blockade, myeloid-targeted therapy, and immune agonist therapy.
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Affiliation(s)
- Eileen Carpenter
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
| | - Sarah Nelson
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Filip Bednar
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Clifford Cho
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Hari Nathan
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Vaibhav Sahai
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Timothy L Frankel
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
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