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Yuan Z, Fang K, Miao X, Zhang Y, Gu M, Xu W, Li H, Zhu D, Zhou J, Sun J, Gu X. Investigating the mechanisms by which low NAT1 expression in tumor cells contributes to chemo-resistance in colorectal cancer. Clin Epigenetics 2025; 17:77. [PMID: 40329330 PMCID: PMC12053866 DOI: 10.1186/s13148-025-01882-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 04/11/2025] [Indexed: 05/08/2025] Open
Abstract
BACKGROUND In the therapeutic landscape of colorectal cancer (CRC), chemo-resistance poses a significant and prevalent obstacle that complicates treatment efficacy and patient outcomes. Over time, cancer cells can develop mechanisms to resist the toxic effects of chemo-therapy drugs, leading to reduced sensitivity or complete insensitivity to these agents. The enzyme Arylamine N-acetyltransferase 1 (NAT1) has emerged as a promising target in strategies aimed at overcoming this challenge. NAT1 is involved in the metabolism of various xenobiotics, including some chemotherapeutic agents. Understanding the complex interactions between NAT1 and chemotherapeutic agents, as well as the molecular mechanisms underlying chemo-resistance, is crucial for the development of novel therapeutic approaches. OBJECTIVE This study aimed to assess the role of NAT1 in mediating chemo-resistance in CRC, with the goal of identifying novel strategies to overcome this clinical challenge. METHODS We conducted a comprehensive analysis using various bioinformatics tools and in vitro experiments to evaluate the effect of NAT1 expression on chemo-resistance in CRC. Furthermore, we employed a multi-omics approach, including metabolomics and next-generation sequencing, to uncover the mechanisms by which NAT1 influences chemo-resistance. Additionally, we utilized single-cell RNA sequencing (scRNA-seq), the Cellchat assay, and western blot to explore the intercellular communication between tumor and endothelial cells in the context of anti-PD-1 therapy and NAT1's impact. RESULTS Our study reveals that decreased NAT1 expression in CRC tumor tissues, relative to adjacent normal tissues, is significantly associated with a poorer patient prognosis. Experimental data indicate that silencing NAT1 in CaCO2 and HCT116 cell lines results in heightened resistance to five chemotherapeutic agents: vinblastine, docetaxel, gemcitabine, vincristine, and daporinad. Additionally, NAT1 silencing increases the proportion of LGR5+ cells, which are known to be chemo-resistant. Our research further revealed that exposure to these five drugs induces a decrease in NAT1 expression within CRC cells. Mechanistic insights show that NAT1 knockdown triggers a metabolic reprogramming in CRC cells, shifting from oxidative phosphorylation and the tricarboxylic acid cycle to a preference for glycolysis. Furthermore, silencing of NAT1 in CRC cells leads to an up-regulation of VEGFA expression. Notably, the application of anti-PD-1 therapy was demonstrated to significantly disrupt the VEGFA-VEGFR axis signaling, an interaction critical between CRC cells and endothelial cells. This discovery underscores the potential of targeting the VEGFA pathway as a therapeutic approach to mitigate the adverse effects associated with NAT1 down-regulation in CRC. CONCLUSION Our study underscores the multifaceted role of NAT1 in modulating chemo-sensitivity, cellular metabolism, and angiogenesis in CRC. These findings position NAT1 as a compelling candidate for a biomarker and a potential therapeutic target, offering new avenues for CRC management.
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Affiliation(s)
- Zheng Yuan
- Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China
| | - Kai Fang
- College of Basic Medical Sciences, Suzhou University, Suzhou, China
| | - Xinsheng Miao
- Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China
| | - Yan Zhang
- Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China
| | - Menghui Gu
- Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China
| | - Wei Xu
- Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China
| | - Hao Li
- Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China
| | - Dawei Zhu
- Nanjing Medical University, Suzhou, China
| | - Jiahui Zhou
- Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China.
| | - Jian Sun
- Affiliated Suzhou Hospital of Nanjing Medical University, Center for Reproduction and Genetics of Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China.
| | - Xinhua Gu
- Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School of Nanjing Medical University, Suzhou, China.
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Yuan Z, Fang K, Miao X, Zhang Y, Gu M, Xu W, Li H, Zhu D, Zhou J, Sun J, Gu X. Investigating the mechanisms by which low NAT1 expression in tumor cells contributes to chemo-resistance in colorectal cancer. Clin Epigenetics 2025; 17:77. [DOI: doi.org/10.1186/s13148-025-01882-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 04/11/2025] [Indexed: 05/20/2025] Open
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3
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Mathiesen H, Juul-Madsen K, Tramm T, Vorup-Jensen T, Møller HJ, Etzerodt A, Andersen MN. Prognostic value of CD163 + macrophages in solid tumor malignancies: A scoping review. Immunol Lett 2025; 272:106970. [PMID: 39778658 DOI: 10.1016/j.imlet.2025.106970] [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: 11/12/2024] [Revised: 12/19/2024] [Accepted: 01/02/2025] [Indexed: 01/11/2025]
Abstract
Tumor-associated macrophages (TAMs) play crucial roles in development and progression of malignant diseases. Notably, CD163+ TAMs likely perform specific pro-tumorigenic functions, suggesting that this subset may serve as both prognostic biomarkers and targets for future anti-cancer therapy. We conducted a scoping review to map the current knowledge on the prognostic role of CD163+ TAMs in the five most lethal cancers worldwide: Lung, colorectal, gastric, liver, and breast cancer. For all cancer types, most studies showed that high tumoral presence of CD163+ cells was associated with poor patient outcome, and this association was more frequently observed when CD163+ cells were measured at the tumor periphery compared to more central parts of the tumor. These results support that CD163+ TAMs represent a biomarker of poor patient outcome across a variety of solid tumors, and highlight the relevance of further investigations of CD163+ TAMs as targets of future immunotherapies.
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Affiliation(s)
- Henriette Mathiesen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark
| | - Kristian Juul-Madsen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark; Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
| | - Trine Tramm
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Holger Jon Møller
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Anders Etzerodt
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Morten Nørgaard Andersen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
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4
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Yuan W, Zhang J, Chen H, Zhuang Y, Zhou H, Li W, Qiu W, Zhou H. Natural compounds modulate the mechanism of action of tumour-associated macrophages against colorectal cancer: a review. J Cancer Res Clin Oncol 2024; 150:502. [PMID: 39546016 PMCID: PMC11568041 DOI: 10.1007/s00432-024-06022-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 10/28/2024] [Indexed: 11/17/2024]
Abstract
Colorectal cancer (CRC) exhibits a substantial morbidity and mortality rate, with its aetiology and pathogenesis remain elusive. It holds significant importance within the tumour microenvironment (TME) and exerts a crucial regulatory influence on tumorigenesis, progression, and metastasis. TAMs possess the capability to foster CRC pathogenesis, proliferation, invasion, and metastasis, as well as angiogenesis, immune evasion, and tumour resistance. Furthermore, TAMs can mediate the prognosis of CRC. In this paper, we review the mechanisms by which natural compounds target TAMs to exert anti-CRC effects from the perspective of the promotional effects of TAMs on CRC, mainly regulating the polarization of TAMs, reducing the infiltration and recruitment of TAMs, enhancing the phagocytosis of macrophages, and regulating the signalling pathways and cytokines, and discuss the potential value and therapeutic strategies of natural compounds-targeting the TAMs pathway in CRC clinical treatment.
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Affiliation(s)
- Weichen Yuan
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiexiang Zhang
- Urology Centre, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Surgery of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Haibin Chen
- Science and Technology Department, Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yupei Zhuang
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Hongli Zhou
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenting Li
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Wenli Qiu
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Hongguang Zhou
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
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5
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Fan Q, Fu ZW, Xu M, Lv F, Shi JS, Zeng QQ, Xiong DH. Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer. World J Gastrointest Oncol 2024; 16:4064-4079. [DOI: 10.4251/wjgo.v16.i10.4064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 08/03/2024] [Accepted: 08/16/2024] [Indexed: 09/26/2024] Open
Abstract
The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
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Affiliation(s)
- Qi Fan
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Zheng-Wei Fu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Ming Xu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Feng Lv
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Jia-Song Shi
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Qi-Qi Zeng
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - De-Hai Xiong
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
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6
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Huang R, Kang T, Chen S. The role of tumor-associated macrophages in tumor immune evasion. J Cancer Res Clin Oncol 2024; 150:238. [PMID: 38713256 PMCID: PMC11076352 DOI: 10.1007/s00432-024-05777-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 05/03/2024] [Indexed: 05/08/2024]
Abstract
BACKGROUND Tumor growth is closely linked to the activities of various cells in the tumor microenvironment (TME), particularly immune cells. During tumor progression, circulating monocytes and macrophages are recruited, altering the TME and accelerating growth. These macrophages adjust their functions in response to signals from tumor and stromal cells. Tumor-associated macrophages (TAMs), similar to M2 macrophages, are key regulators in the TME. METHODS We review the origins, characteristics, and functions of TAMs within the TME. This analysis includes the mechanisms through which TAMs facilitate immune evasion and promote tumor metastasis. Additionally, we explore potential therapeutic strategies that target TAMs. RESULTS TAMs are instrumental in mediating tumor immune evasion and malignant behaviors. They release cytokines that inhibit effector immune cells and attract additional immunosuppressive cells to the TME. TAMs primarily target effector T cells, inducing exhaustion directly, influencing activity indirectly through cellular interactions, or suppressing through immune checkpoints. Additionally, TAMs are directly involved in tumor proliferation, angiogenesis, invasion, and metastasis. Developing innovative tumor-targeted therapies and immunotherapeutic strategies is currently a promising focus in oncology. Given the pivotal role of TAMs in immune evasion, several therapeutic approaches have been devised to target them. These include leveraging epigenetics, metabolic reprogramming, and cellular engineering to repolarize TAMs, inhibiting their recruitment and activity, and using TAMs as drug delivery vehicles. Although some of these strategies remain distant from clinical application, we believe that future therapies targeting TAMs will offer significant benefits to cancer patients.
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Affiliation(s)
- Ruizhe Huang
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Ting Kang
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
| | - Siyu Chen
- Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
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7
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McWhorter R, Bonavida B. The Role of TAMs in the Regulation of Tumor Cell Resistance to Chemotherapy. Crit Rev Oncog 2024; 29:97-125. [PMID: 38989740 DOI: 10.1615/critrevoncog.2024053667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2024]
Abstract
Tumor-associated macrophages (TAMs) are the predominant cell infiltrate in the immunosuppressive tumor microenvironment (TME). TAMs are central to fostering pro-inflammatory conditions, tumor growth, metastasis, and inhibiting therapy responses. Many cancer patients are innately refractory to chemotherapy and or develop resistance following initial treatments. There is a clinical correlation between the level of TAMs in the TME and chemoresistance. Hence, the pivotal role of TAMs in contributing to chemoresistance has garnered significant attention toward targeting TAMs to reverse this resistance. A prerequisite for such an approach requires a thorough understanding of the various underlying mechanisms by which TAMs inhibit response to chemotherapeutic drugs. Such mechanisms include enhancing drug efflux, regulating drug metabolism and detoxification, supporting cancer stem cell (CSCs) resistance, promoting epithelial-mesenchymal transition (EMT), inhibiting drug penetration and its metabolism, stimulating angiogenesis, impacting inhibitory STAT3/NF-κB survival pathways, and releasing specific inhibitory cytokines including TGF-β and IL-10. Accordingly, several strategies have been developed to overcome TAM-modulated chemoresistance. These include novel therapies that aim to deplete TAMs, repolarize them toward the anti-tumor M1-like phenotype, or block recruitment of monocytes into the TME. Current results from TAM-targeted treatments have been unimpressive; however, the use of TAM-targeted therapies in combination appears promising These include targeting TAMs with radiotherapy, chemotherapy, chemokine receptor inhibitors, immunotherapy, and loaded nanoparticles. The clinical limitations of these strategies are discussed.
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Affiliation(s)
| | - Benjamin Bonavida
- Department of Microbiology, Immunology, & Molecular Genetics, David Geffen School of Medicine at UCLA, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747, USA
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8
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Dubey S, Ghosh S, Goswami D, Ghatak D, De R. Immunometabolic attributes and mitochondria-associated signaling of Tumor-Associated Macrophages in tumor microenvironment modulate cancer progression. Biochem Pharmacol 2023; 208:115369. [PMID: 36481347 DOI: 10.1016/j.bcp.2022.115369] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/24/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
Macrophages are specialized immune cells, which have the capacity to phagocytize and destroy the target cells, including tumor cells. Some macrophages, however on their way to devour the cancer cells undergo a change due to a complex set of signaling pathways. They are induced to change into a polarized state known as M2. The M2 macrophages help in metastasis, tumor suppression, and angiogenesis. The macrophage which gets associated with this TME, are referred to as tumor-associated macrophages (TAMs). TAMS undergo a metabolic reprogramming toward oxidative metabolism for bioenergetic purposes (OXPHOS), fatty acid oxidation (FAO), decreased glycolysis, decreased metabolism via the PPP, and upregulation of arginase 1 (ARG1) which triggers immunosuppressive pro-tumor signaling in the tumor microenvironment (TME) in which mitochondria plays an instrumental role. Reports have suggested that a complex series of interactions and exchange of materials, such as cytokines, metabolic intermediates and sometimes even transfer of mitochondria take place between TAMS and other TME components most importantly cancer cells that reprogram their metabolism to encourage cell growth, division, epithelial to mesenchymal transition, that ultimately play an important role in tumor progression. This review will try to focus on the crosstalk between the TAMs with several other components of TME, what instrumental role mitochondria play in that and also try to explore some of the therapeutic options available in cancer patients.
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Affiliation(s)
- Srijan Dubey
- Amity Institute of Biotechnology, Amity University, Kolkata, Plot No: 36, 37 & 38, Major Arterial Road, Action Area II, Kadampukur Village, Newtown, Kolkata 700135, West Bengal, India
| | - Sayak Ghosh
- Amity Institute of Biotechnology, Amity University, Kolkata, Plot No: 36, 37 & 38, Major Arterial Road, Action Area II, Kadampukur Village, Newtown, Kolkata 700135, West Bengal, India
| | - Debosmita Goswami
- Amity Institute of Biotechnology, Amity University, Kolkata, Plot No: 36, 37 & 38, Major Arterial Road, Action Area II, Kadampukur Village, Newtown, Kolkata 700135, West Bengal, India
| | - Debapriya Ghatak
- Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
| | - Rudranil De
- Amity Institute of Biotechnology, Amity University, Kolkata, Plot No: 36, 37 & 38, Major Arterial Road, Action Area II, Kadampukur Village, Newtown, Kolkata 700135, West Bengal, India.
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9
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Gazzillo A, Polidoro MA, Soldani C, Franceschini B, Lleo A, Donadon M. Relationship between Epithelial-to-Mesenchymal Transition and Tumor-Associated Macrophages in Colorectal Liver Metastases. Int J Mol Sci 2022; 23:16197. [PMID: 36555840 PMCID: PMC9783529 DOI: 10.3390/ijms232416197] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/13/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
The liver is the most common metastatic site in colorectal cancer (CRC) patients. Indeed, 25-30% of the cases develop colorectal liver metastasis (CLM), showing an extremely poor 5-year survival rate and resistance to conventional anticancer therapies. Tumor-associated macrophages (TAMs) provide a nurturing microenvironment for CRC metastasis, promoting epithelial-to-mesenchymal transition (EMT) through the TGF-β signaling pathway, thus driving tumor cells to acquire mesenchymal properties that allow them to migrate from the primary tumor and invade the new metastatic site. EMT is known to contribute to the disruption of blood vessel integrity and the generation of circulating tumor cells (CTCs), thus being closely related to high metastatic potential in numerous solid cancers. Despite the fact that it is well-recognized that the crosstalk between tumor cells and the inflammatory microenvironment is crucial in the EMT process, the association between the EMT and the role of TAMs is still poorly understood. In this review, we elaborated on the role that TAMs exert in the induction of EMT during CLM development. Since TAMs are the major source of TGF-β in the liver, we also focused on novel insights into their role in TGF-β-induced EMT.
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Affiliation(s)
- Aurora Gazzillo
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Michela Anna Polidoro
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Cristiana Soldani
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Barbara Franceschini
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Ana Lleo
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, MI, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
| | - Matteo Donadon
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, MI, Italy
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, NO, Italy
- Department of General Surgery, University Maggiore Hospital Della Carità, 28100 Novara, NO, Italy
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Deng Z, Wu N, Suo Q, Wang J, Yue Y, Geng L, Zhang Q. Fucoidan, as an immunostimulator promotes M1 macrophage differentiation and enhances the chemotherapeutic sensitivity of capecitabine in colon cancer. Int J Biol Macromol 2022; 222:562-572. [PMID: 36170928 DOI: 10.1016/j.ijbiomac.2022.09.201] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 09/19/2022] [Accepted: 09/22/2022] [Indexed: 01/21/2023]
Abstract
Chemotherapy resistance is one of the most critical challenges in colorectal cancer (CRC) treatment. The occurrence and development of chemotherapy resistance closely related to the tumor immune microenvironment (TIME). As the most important immunosuppressive immune cells infiltrating into the TIME, macrophages are essential for chemotherapy resistance in CRC treatment. In this study, we found that a kind of fucoidan (FPS1M) induced macrophages differentiation to the M1 phenotype, and this transformation promoted cancer cells apoptosis both in vitro and in vivo. TNFα is a key mediator of FPS1M-induced tumorcidal activity of macrophages. Mechanistically, as a stimulator of TLR4, FPS1M enhanced macrophages glycolysis and regulated macrophages differentiation to the M1 phenotype by the activation of TLR4 mediated PI3K/AKT/mTOR signaling axis. In addition, FPS1M improved the immunosuppressed tumor microenvironment by increasing the infiltration of M1 macrophages in tumor tissue, which was conducive to improving the sensitivity of tumor to chemotherapy. Collectively, our findings demonstrated that FPS1M has the great potential to be used in tumor immunotherapy. The results also suggested that the combination of FPS1M with capecitabine is an alternative therapy method for colon cancer.
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Affiliation(s)
- Zhenzhen Deng
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Lab for Marine Biology and Biotechnology, Qingdao National Lab for Marine Sci. & Tech, Qingdao 266071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ning Wu
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Laboratory for Marine drugs and biological products, Pilot National Laboratory for Marine Science and Technology, Qingdao, China.
| | - Qishan Suo
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Lab for Marine Biology and Biotechnology, Qingdao National Lab for Marine Sci. & Tech, Qingdao 266071, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jing Wang
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Lab for Marine Biology and Biotechnology, Qingdao National Lab for Marine Sci. & Tech, Qingdao 266071, China
| | - Yang Yue
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Lab for Marine Biology and Biotechnology, Qingdao National Lab for Marine Sci. & Tech, Qingdao 266071, China
| | - Lihua Geng
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Lab for Marine Biology and Biotechnology, Qingdao National Lab for Marine Sci. & Tech, Qingdao 266071, China
| | - Quanbin Zhang
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Center for Ocean Mega-Science, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China; Lab for Marine Biology and Biotechnology, Qingdao National Lab for Marine Sci. & Tech, Qingdao 266071, China.
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11
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Prayugo FB, Kao TJ, Anuraga G, Ta HDK, Chuang JY, Lin LC, Wu YF, Wang CY, Lee KH. Expression Profiles and Prognostic Value of FABPs in Colorectal Adenocarcinomas. Biomedicines 2021; 9:1460. [PMID: 34680577 PMCID: PMC8533171 DOI: 10.3390/biomedicines9101460] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 10/04/2021] [Accepted: 10/06/2021] [Indexed: 01/04/2023] Open
Abstract
Colorectal cancer (CRC) is one of the world's leading causes of cancer-related deaths; thus, it is important to detect it as early as possible. Obesity is thought to be linked to a large rise in the CRC incidence as a result of bad dietary choices, such as a high intake of animal fats. Fatty acid-binding proteins (FABPs) are a set of molecules that coordinate intracellular lipid responses and are highly associated with metabolism and inflammatory pathways. There are nine types of FABP genes that have been found in mammals, which are FABP1-7, FABP9, and FABP12. Each FABP gene has its own roles in different organs of the body; hence, each one has different expression levels in different cancers. The roles of FABP family genes in the development of CRC are still poorly understood. We used a bioinformatics approach to examine FABP family gene expression profiles using the Oncomine, GEPIA, PrognoScan, STRING, cBioPortal, MetaCore, and TIMER platforms. Results showed that the FABP6 messenger (m)RNA level is overexpressed in CRC cells compared to normal cells. The overexpression of FABP6 was found to be related to poor prognosis in CRC patients' overall survival. The immunohistochemical results in the Human Protein Atlas showed that FABP1 and FABP6 exhibited strong staining in CRC tissues. An enrichment analysis showed that high expression of FABP6 was significantly correlated with the role of microRNAs in cell proliferation in the development of CRC through the insulin-like growth factor (IGF) signaling pathway. FABP6 functions as an intracellular bile-acid transporter in the ileal epithelium. We looked at FABP6 expression in CRC since bile acids are important in the carcinogenesis of CRC. In conclusion, high FABP6 expression is expected to be a potential biomarker for detecting CRC at the early stage.
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Affiliation(s)
- Fidelia Berenice Prayugo
- International Master/PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; (G.A.); (H.D.K.T.); (L.-C.L.)
| | - Tzu-Jen Kao
- The PhD Program for Neural Regenerative Medicine, Taipei Medical University, Taipei 11031, Taiwan; (T.-J.K.); (J.-Y.C.)
- Research Center of Neuroscience, Taipei Medical University, Taipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Gangga Anuraga
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; (G.A.); (H.D.K.T.); (L.-C.L.)
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
- Department of Statistics, Faculty of Science and Technology, Universitas PGRI Adi Buana, Surabaya 60234, East Java, Indonesia
| | - Hoang Dang Khoa Ta
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; (G.A.); (H.D.K.T.); (L.-C.L.)
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | - Jian-Ying Chuang
- The PhD Program for Neural Regenerative Medicine, Taipei Medical University, Taipei 11031, Taiwan; (T.-J.K.); (J.-Y.C.)
- Research Center of Neuroscience, Taipei Medical University, Taipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Li-Chia Lin
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; (G.A.); (H.D.K.T.); (L.-C.L.)
| | - Yung-Fu Wu
- National Defense Medical Center, Department of Medical Research, School of Medicine, Tri-Service General Hospital, Taipei 11490, Taiwan;
| | - Chih-Yang Wang
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; (G.A.); (H.D.K.T.); (L.-C.L.)
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | - Kuen-Haur Lee
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; (G.A.); (H.D.K.T.); (L.-C.L.)
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
- Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan
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