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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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Jia Y, Zhu H, Cai X, Sun C, Ye Y, Cai D, Yang S, Cheng J, Gao J, Yang Y, Zeng H, Zou Q, Li J, Sun H, Wang W. Plant-Derived Immunomodulatory Nanoadjuvants for Cancer Vaccines: Current Status and Future Opportunities. Vaccines (Basel) 2025; 13:378. [PMID: 40333256 PMCID: PMC12031155 DOI: 10.3390/vaccines13040378] [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: 02/07/2025] [Revised: 03/26/2025] [Accepted: 03/28/2025] [Indexed: 05/09/2025] Open
Abstract
Cancer is a major cause of death worldwide, and vaccine administration is an effective way to stimulate immune responses in patients and to achieve preventive and therapeutic effects. Few vaccines have been used in clinical settings because they have poor immunogenicity, and it is difficult to induce a robust immune response in patients. An adjuvant is an important component of a vaccine that can enhance the intensity, speed, and duration of immune responses. The achievements of adjuvants in the production of stable, safe, and immunogenic tumor vaccines have aroused the enthusiasm of researchers. Recent results have suggested that plant-derived adjuvants have unique advantages, such as greatly improving immune responses to cancer vaccines and promoting humoral and cellular immunity with good biocompatibility and biodegradability. When these adjuvants are used in combination with vaccines, they can not only activate the immune response in vivo but can also promote cytokine secretion and accelerate dendritic cell maturation. This review focused on the application progress of plant adjuvants, including saponins, polysaccharides, flavonoids, and plant virus-like particles, and their combination with nano-delivery systems in cancer vaccines. At the same time, we have also discussed the immunomodulatory mechanisms of these adjuvants and their prospects for improving vaccine efficacy in the treatment of cancer in the future. These promising plant adjuvants may provide prospects and a research basis for the development of tumor vaccines.
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Affiliation(s)
- Yimin Jia
- Chongqing University Cancer Hospital, Chongqing 400030, China;
| | - Hui Zhu
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; (H.Z.); (X.C.); (C.S.); (Y.Y.); (D.C.); (S.Y.); (J.C.); (J.G.); (Y.Y.); (H.Z.); (Q.Z.)
| | - Xinyu Cai
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; (H.Z.); (X.C.); (C.S.); (Y.Y.); (D.C.); (S.Y.); (J.C.); (J.G.); (Y.Y.); (H.Z.); (Q.Z.)
| | - Cun Sun
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; (H.Z.); (X.C.); (C.S.); (Y.Y.); (D.C.); (S.Y.); (J.C.); (J.G.); (Y.Y.); (H.Z.); (Q.Z.)
| | - Yan Ye
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; (H.Z.); (X.C.); (C.S.); (Y.Y.); (D.C.); (S.Y.); (J.C.); (J.G.); (Y.Y.); (H.Z.); (Q.Z.)
| | - Dingyi Cai
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; (H.Z.); (X.C.); (C.S.); (Y.Y.); (D.C.); (S.Y.); (J.C.); (J.G.); (Y.Y.); (H.Z.); (Q.Z.)
- Department of Stomatology, The 79th Group Army Hospital of PLA, Liaoyang 111000, China
| | - Shuaifei Yang
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; (H.Z.); (X.C.); (C.S.); (Y.Y.); (D.C.); (S.Y.); (J.C.); (J.G.); (Y.Y.); (H.Z.); (Q.Z.)
| | - Jingjing Cheng
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; (H.Z.); (X.C.); (C.S.); (Y.Y.); (D.C.); (S.Y.); (J.C.); (J.G.); (Y.Y.); (H.Z.); (Q.Z.)
| | - Jining Gao
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; (H.Z.); (X.C.); (C.S.); (Y.Y.); (D.C.); (S.Y.); (J.C.); (J.G.); (Y.Y.); (H.Z.); (Q.Z.)
| | - Yun Yang
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; (H.Z.); (X.C.); (C.S.); (Y.Y.); (D.C.); (S.Y.); (J.C.); (J.G.); (Y.Y.); (H.Z.); (Q.Z.)
| | - Hao Zeng
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; (H.Z.); (X.C.); (C.S.); (Y.Y.); (D.C.); (S.Y.); (J.C.); (J.G.); (Y.Y.); (H.Z.); (Q.Z.)
| | - Quanming Zou
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; (H.Z.); (X.C.); (C.S.); (Y.Y.); (D.C.); (S.Y.); (J.C.); (J.G.); (Y.Y.); (H.Z.); (Q.Z.)
| | - Jieping Li
- Affiliated Nanhua Hospital of University of South China, Hengyang 421002, China;
| | - Hongwu Sun
- Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; (H.Z.); (X.C.); (C.S.); (Y.Y.); (D.C.); (S.Y.); (J.C.); (J.G.); (Y.Y.); (H.Z.); (Q.Z.)
| | - Wenxiu Wang
- Shandong Binzhou Animal Science and Veterinary Medicine Academy, Binzhou 256600, China
- Shandong Academician Workstation, Binzhou 256600, China
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Siqin S, Nikitina E, Rahbari M, Ernst C, Krunic D, Birgin E, Tessmer C, Hofmann I, Rahbari N, Bund T. Bovine Meat and Milk Factor (BMMF) Protein Is Expressed in Macrophages Spread Widely over the Mucosa of Colorectal Cancer Patients. Cells 2025; 14:455. [PMID: 40136704 PMCID: PMC11940877 DOI: 10.3390/cells14060455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 02/27/2025] [Accepted: 03/17/2025] [Indexed: 03/27/2025] Open
Abstract
Red meat consumption is considered a risk factor for colorectal cancer (CRC) development and stimulated isolation of plasmid-like DNA molecules from bovine serum and milk, termed bovine meat and milk factors (BMMFs). BMMFs encode a conserved replication protein (Rep). Increased populations of Rep-expressing macrophages have been identified in the peritumor of CRC patients and pre-cancerous tissues when compared to the tissues of healthy individuals. This supports the concept that BMMFs increase cancer risk by indirect carcinogenesis, upon induction of chronic inflammation. However, the spread of Rep+ immune cells in tissues at greater distances from primary tumors has not yet been assessed. Here, we immunohistologically analyzed the presence of Rep+ immune cells in sets of tumor, peritumor and, additionally, distant tissues of CRC patients (n = 13). We identified consistently high numbers of BMMF-positive macrophages in mucosal tissues at distances of as much as 25 cm away from the primary tumors, at levels comparable to peritumors and associated with M2-like macrophage polarization. The broad distribution of BMMFs suggests that BMMF+ macrophages might already exist at stages of pre-cancerous dysplasia or before. Quantification of BMMF tissue expression during colonoscopy might help to preventively stratify individuals at risk of developing polyps/CRC and recommend them for enhanced surveillance and/or changes in dietary lifestyle.
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Affiliation(s)
- Sumen Siqin
- Division of Episomal-Persistent DNA in Cancer- and Chronic Diseases, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Ekaterina Nikitina
- Division of Episomal-Persistent DNA in Cancer- and Chronic Diseases, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Mohammad Rahbari
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, University of Tuebingen, 72076 Tuebingen, Germany
| | - Claudia Ernst
- Division of Episomal-Persistent DNA in Cancer- and Chronic Diseases, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Damir Krunic
- Light Microscopy Facility, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Emrullah Birgin
- Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- Clinic for General and Visceral Surgery, University Hospital Ulm, 89081 Ulm, Germany
| | - Claudia Tessmer
- Core Facility Antibodies, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Ilse Hofmann
- Core Facility Antibodies, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Nuh Rahbari
- Department of Surgery, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- Clinic for General and Visceral Surgery, University Hospital Ulm, 89081 Ulm, Germany
| | - Timo Bund
- Division of Episomal-Persistent DNA in Cancer- and Chronic Diseases, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Yang S, Bai Z, Zhang F, Cui W, Bu P, Bai W, Xi Y. Expression and prognostic significance of CD93 in blood vessels in colorectal cancer: an immunohistochemical analysis of 134 cases. BMC Gastroenterol 2025; 25:84. [PMID: 39962383 PMCID: PMC11834615 DOI: 10.1186/s12876-025-03643-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 01/22/2025] [Indexed: 02/20/2025] Open
Abstract
OBJECTIVE Tumor blood vessels are tortuous and dilated, contributing to the aberrant tumor microenvironment. CD93 is a newly reported transmembrane receptor, mainly expressed in tumor endothelial cells, that has demonstrated prognostic value in some cancer types. However, the role of CD93 in the vasculature of colorectal cancer (CRC) tissues and its prognostic significance remain unknown. It is therefore necessary to explore the effect of CD93 in patients with CRC. METHOD We detected the expression of CD93 in human CRC tissues using immunohistochemistry. We then examined the correlation between CD93 expression and clinicopathological factors in cancer tissues from 134 patients with CRC. RESULT CD93 expression levels were higher in CRC vessels than in vessels in adjacent normal tissues. Upregulation of CD93 was associated with tumor site and microsatellite instability. CD93 protein expression was positively related to macrophage infiltration in CRC. High expression of CD93 may indicate normalization of the tumor vasculature and was associated with better overall survival. CONCLUSION CD93 was highly expressed in CRC vessels and correlated with infiltration of immune cells. Our findings reveal that vascular normalization and patient prognosis can be predicted by detecting CD93 expression in CRC tumor tissues.
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Affiliation(s)
- Shuzhe Yang
- Second Clinical Medical School, Shanxi Medical University, Taiyuan, China
| | - Zhongyuan Bai
- First Clinical Medical School, Shanxi Medical University, Taiyuan, China
| | - Fei Zhang
- Department of Pathology, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hosipital, Chinese Academy of Medical Sciences/ Cancer Hospital Affiliated to Shanxi Medical University, No. 3, ZhiGongXinCun Street, Taiyuan, China
| | - Wei Cui
- Department of Pathology, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hosipital, Chinese Academy of Medical Sciences/ Cancer Hospital Affiliated to Shanxi Medical University, No. 3, ZhiGongXinCun Street, Taiyuan, China
| | - Peng Bu
- Department of Pathology, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hosipital, Chinese Academy of Medical Sciences/ Cancer Hospital Affiliated to Shanxi Medical University, No. 3, ZhiGongXinCun Street, Taiyuan, China
| | - Wenqi Bai
- Department of General Surgery Sciences, Cancer Hospital, Shanxi Province Cancer Hospital/ShanxiHospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to ShanxiMedical University, No. 3, ZhiGongXinCun Street, Taiyuan, China.
| | - Yanfeng Xi
- Department of Pathology, Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hosipital, Chinese Academy of Medical Sciences/ Cancer Hospital Affiliated to Shanxi Medical University, No. 3, ZhiGongXinCun Street, Taiyuan, China.
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Liu Q, Liao L. Identification of macrophage-related molecular subgroups and risk signature in colorectal cancer based on a bioinformatics analysis. Autoimmunity 2024; 57:2321908. [PMID: 38466182 DOI: 10.1080/08916934.2024.2321908] [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: 02/17/2024] [Indexed: 03/12/2024]
Abstract
Macrophages play a crucial role in tumor initiation and progression, while macrophage-associated gene signature in colorectal cancer (CRC) patients has not been investigated. Our study aimed to identify macrophage-related molecular subgroups and develop a macrophage-related risk model to predict CRC prognosis. The mRNA expression profile and clinical information of CRC patients were obtained from TCGA and GEO databases. CRC patients from TCGA were divided into high and low macrophage subgroups based on the median macrophage score. The ESTIMATE and CIBERSORT algorithms were used to assess immune cell infiltration between subgroups. GSVA and GSEA analyses were performed to investigate differences in enriched pathways between subgroups. Univariate and LASSO Cox regression were used to build a prognostic risk model, which was further validated in the GSE39582 dataset. A high macrophage score subgroup was associated with poor prognosis, highly activated immune-related pathways and an immune-active microenvironment. A total of 547 differentially expressed macrophage-related genes (DEMRGs) were identified, among which seven genes (including RIMKLB, UST, PCOLCE2, ZNF829, TMEM59L, CILP2, DTNA) were identified by COX regression analyses and used to build a risk score model. The risk model shows good predictive and diagnostic values for CRC patients in both TCGA and GSE39852 datasets. Furthermore, multivariate Cox regression analysis showed that the risk score was an independent risk factor for overall survival in CRC patients. Our findings provided a novel insight into macrophage heterogeneity and its immunological role in CRC. This risk score model may serve as an effective prognostic tool and contribute to personalised clinical management of CRC patients.
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Affiliation(s)
- Qi Liu
- Department of General Surgery, Heyuan People's Hospital, Heyuan, China
| | - Li Liao
- Department of preventive health care, Heyuan People's Hospital, Heyuan, China
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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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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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Li MY, Ye W, Luo KW. Immunotherapies Targeting Tumor-Associated Macrophages (TAMs) in Cancer. Pharmaceutics 2024; 16:865. [PMID: 39065562 PMCID: PMC11280177 DOI: 10.3390/pharmaceutics16070865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/17/2024] [Accepted: 06/21/2024] [Indexed: 07/28/2024] Open
Abstract
Tumor-associated macrophages (TAMs) are one of the most plentiful immune compositions in the tumor microenvironment, which are further divided into anti-tumor M1 subtype and pro-tumor M2 subtype. Recent findings found that TAMs play a vital function in the regulation and progression of tumorigenesis. Moreover, TAMs promote tumor vascularization, and support the survival of tumor cells, causing an impact on tumor growth and patient prognosis. Numerous studies show that reducing the density of TAMs, or modulating the polarization of TAMs, can inhibit tumor growth, indicating that TAMs are a promising target for tumor immunotherapy. Recently, clinical trials have found that treatments targeting TAMs have achieved encouraging results, and the U.S. Food and Drug Administration has approved a number of drugs for use in cancer treatment. In this review, we summarize the origin, polarization, and function of TAMs, and emphasize the therapeutic strategies targeting TAMs in cancer treatment in clinical studies and scientific research, which demonstrate a broad prospect of TAMs-targeted therapies in tumor immunotherapy.
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Affiliation(s)
- Mei-Ye Li
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; (M.-Y.L.); (W.Y.)
| | - Wei Ye
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; (M.-Y.L.); (W.Y.)
| | - Ke-Wang Luo
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; (M.-Y.L.); (W.Y.)
- People’s Hospital of Longhua, The affiliated hospital of Southern Medical University, Shenzhen 518109, China
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Sun J, Luo J, Jiang F, Zhao J, Zhou S, Wang L, Zhang D, Ding Y, Li X. Exploring the cross-cancer effect of circulating proteins and discovering potential intervention targets for 13 site-specific cancers. J Natl Cancer Inst 2024; 116:565-573. [PMID: 38039160 DOI: 10.1093/jnci/djad247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/23/2023] [Accepted: 11/20/2023] [Indexed: 12/03/2023] Open
Abstract
BACKGROUND The proteome is an important reservoir of potential therapeutic targets for cancer. This study aimed to examine the causal associations between plasma proteins and cancer risk and to identify proteins with cross-cancer effects. METHODS Genetic instruments for 3991 plasma proteins were extracted from a large-scale proteomic study. Summary-level data of 13 site-specific cancers were derived from publicly available datasets. Proteome-wide Mendelian randomization and colocalization analyses were used to investigate the causal effect of circulating proteins on cancers. Protein-protein interactions and druggability assessment were conducted to prioritize potential therapeutic targets. Finally, systematical Mendelian randomization analysis between healthy lifestyle factors and cancer-related proteins was conducted to identify which proteins could act as interventional targets by lifestyle changes. RESULTS Genetically determined circulating levels of 58 proteins were statistically significantly associated with 7 site-specific cancers. A total of 39 proteins were prioritized by colocalization, of them, 11 proteins (ADPGK, CD86, CLSTN3, CSF2RA, CXCL10, GZMM, IL6R, NCR3, SIGLEC5, SIGLEC14, and TAPBP) were observed to have cross-cancer effects. Notably, 5 of these identified proteins (CD86, CSF2RA, CXCL10, IL6R, and TAPBP) have been targeted for drug development in cancer therapy; 8 proteins (ADPGK, CD86, CXCL10, GZMM, IL6R, SIGLEC5, SIGLEC14, TAPBP) could be modulated by healthy lifestyles. CONCLUSION Our study identified 39 circulating protein biomarkers with convincing causal evidence for 7 site-specific cancers, with 11 proteins demonstrating cross-cancer effects, and prioritized the proteins as potential intervention targets by either drugs or lifestyle changes, which provided new insights into the etiology, prevention, and treatment of cancers.
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Affiliation(s)
- Jing Sun
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jia Luo
- Department of Epidemiology and Health Statistics, the School of Public Health of Qingdao University, Qingdao, Shandong Province, China
| | - Fangyuan Jiang
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jianhui Zhao
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Siyun Zhou
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Lijuan Wang
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK
| | - Dongfeng Zhang
- Department of Epidemiology and Health Statistics, the School of Public Health of Qingdao University, Qingdao, Shandong Province, China
| | - Yuan Ding
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xue Li
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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10
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Osei GY, Adu-Amankwaah J, Koomson S, Beletaa S, Asiamah EA, Smith-Togobo C, Razak SRA. MicroRNAs and colorectal cancer: clinical potential and regulatory networks. Mol Biol Rep 2023; 50:9575-9585. [PMID: 37776413 DOI: 10.1007/s11033-023-08810-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 09/08/2023] [Indexed: 10/02/2023]
Abstract
Colorectal cancer (CRC) is a serious global health concern, with a high incidence and mortality rate. Although there have been advancements in the early detection and treatment of CRC, therapy resistance is common. MicroRNAs (miRNAs), a type of small non-coding RNA that regulates gene expression, are key players in the initiation and progression of CRC. Recently, there has been growing attention to the complex interplay of miRNAs in cancer development. miRNAs are powerful RNA molecules that regulate gene expression and have been implicated in various physiological and pathological processes, including carcinogenesis. By identifying current challenges and limitations of treatment strategies and suggesting future research directions, this review aims to contribute to ongoing efforts to enhance CRC diagnosis and treatment. It also provides a comprehensive overview of the role miRNAs play in CRC carcinogenesis and explores the potential of miRNA-based therapies as a treatment option. Importantly, this review highlights the exciting potential of targeted modulation of miRNA function as a therapeutic approach for CRC.
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Affiliation(s)
- George Yiadom Osei
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Pulau Pinang, 13200, Malaysia
- Department of Medical Laboratory Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Joseph Adu-Amankwaah
- Department of Physiology, Xuzhou Medical University, Xuzhou, People's Republic of China
| | - Selina Koomson
- Department of Medical Laboratory Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Solomon Beletaa
- Department of Medical Laboratory Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Emmanuel Akomanin Asiamah
- Department of Medical Laboratory Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
- Discipline of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, 4001, South Africa
- Cancer and Infectious Diseases Epidemiology Research Unit (CIDERU), College of Health Sciences, University of KwaZulu-Natal, Durban, 4001, South Africa
| | - Cecilia Smith-Togobo
- Department of Medical Laboratory Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Siti Razila Abdul Razak
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Pulau Pinang, 13200, Malaysia.
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11
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Laberiano-Fernandez C, Baldavira CM, Machado-Rugolo J, Tamegnon A, Pandurengan RK, Ab’Saber AM, Balancin ML, Takagaki TY, Nagai MA, Capelozzi VL, Parra ER. The Immunological Landscape of M1 and M2 Macrophages and Their Spatial Distribution in Patients with Malignant Pleural Mesothelioma. Cancers (Basel) 2023; 15:5116. [PMID: 37958292 PMCID: PMC10650059 DOI: 10.3390/cancers15215116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/12/2023] [Accepted: 10/19/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Several tumor-associated macrophages (TAMs) have shown promise as prognosticators in cancer. Our aim was to validate the importance of TAMs in malignant pleural mesothelioma (MPM) using a two-stage design. METHODS We explored The Cancer Genome Atlas (TCGA-MESO) to select immune-relevant macrophage genes in MPM, including M1/M2 markers, as a discovery cohort. This computational cohort was used to create a multiplex immunofluorescence panel. Moreover, a cohort of 68 samples of MPM in paraffin blocks was used to validate the macrophage phenotypes and the co-localization and spatial distribution of these immune cells within the TME and the stromal or tumor compartments. RESULTS The discovery cohort revealed six immune-relevant macrophage genes (CD68, CD86, CD163, CD206, ARG1, CD274), and complementary genes were differentially expressed by M1 and M2 phenotypes with distinct roles in the tumor microenvironment and were associated with the prognosis. In addition, immune-suppressed MPMs with increased enrichment of CD68, CD86, and CD163 genes and high densities of M2 macrophages expressing CD163 and CD206 proteins were associated with worse overall survival (OS). Interestingly, below-median distances from malignant cells to specific M2a and M2c macrophages were associated with worse OS, suggesting an M2 macrophage-driven suppressive component in these tumors. CONCLUSIONS The interactions between TAMs in situ and, particularly, CD206+ macrophages are highly relevant to patient outcomes. High-resolution technology is important for identifying the roles of macrophage populations in tissue specimens and identifying potential therapeutic candidates in MPM.
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Affiliation(s)
- Caddie Laberiano-Fernandez
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (C.L.-F.); (A.T.); (R.K.P.)
| | - Camila Machado Baldavira
- Department of Pathology, Medical School, University of Sao Paulo, Sao Paulo 01246-903, Brazil; (C.M.B.); (J.M.-R.); (A.M.A.); (M.L.B.); (V.L.C.)
| | - Juliana Machado-Rugolo
- Department of Pathology, Medical School, University of Sao Paulo, Sao Paulo 01246-903, Brazil; (C.M.B.); (J.M.-R.); (A.M.A.); (M.L.B.); (V.L.C.)
| | - Auriole Tamegnon
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (C.L.-F.); (A.T.); (R.K.P.)
| | - Renganayaki Krishna Pandurengan
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (C.L.-F.); (A.T.); (R.K.P.)
| | - Alexandre Muxfeldt Ab’Saber
- Department of Pathology, Medical School, University of Sao Paulo, Sao Paulo 01246-903, Brazil; (C.M.B.); (J.M.-R.); (A.M.A.); (M.L.B.); (V.L.C.)
- Division of Pneumology, Instituto do Coração (Incor), Medical School, University of Sao Paulo, Sao Paulo 01246-903, Brazil;
| | - Marcelo Luiz Balancin
- Department of Pathology, Medical School, University of Sao Paulo, Sao Paulo 01246-903, Brazil; (C.M.B.); (J.M.-R.); (A.M.A.); (M.L.B.); (V.L.C.)
- Division of Pneumology, Instituto do Coração (Incor), Medical School, University of Sao Paulo, Sao Paulo 01246-903, Brazil;
| | - Teresa Yae Takagaki
- Division of Pneumology, Instituto do Coração (Incor), Medical School, University of Sao Paulo, Sao Paulo 01246-903, Brazil;
| | - Maria Aparecida Nagai
- Department of Radiology and Oncology, Medical School, University of Sao Paulo, Sao Paulo 01246-903, Brazil;
- Laboratory of Molecular Genetics, Center for Translational Research in Oncology, Cancer Institute of Sao Paulo, Sao Paulo 01246-903, Brazil
| | - Vera Luiza Capelozzi
- Department of Pathology, Medical School, University of Sao Paulo, Sao Paulo 01246-903, Brazil; (C.M.B.); (J.M.-R.); (A.M.A.); (M.L.B.); (V.L.C.)
- Division of Pneumology, Instituto do Coração (Incor), Medical School, University of Sao Paulo, Sao Paulo 01246-903, Brazil;
| | - Edwin Roger Parra
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (C.L.-F.); (A.T.); (R.K.P.)
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12
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Sun J, Zhao J, Jiang F, Wang L, Xiao Q, Han F, Chen J, Yuan S, Wei J, Larsson SC, Zhang H, Dunlop MG, Farrington SM, Ding K, Theodoratou E, Li X. Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome. Genome Med 2023; 15:75. [PMID: 37726845 PMCID: PMC10508028 DOI: 10.1186/s13073-023-01229-9] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 09/08/2023] [Indexed: 09/21/2023] Open
Abstract
BACKGROUND The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) study to identify candidate protein markers and therapeutic targets for colorectal cancer (CRC). METHODS Protein quantitative trait loci (pQTLs) were derived from seven published genome-wide association studies (GWASs) on plasma proteome, and summary-level data were extracted for 4853 circulating protein markers. Genetic associations with CRC were obtained from a large-scale GWAS meta-analysis (16,871 cases and 26,328 controls), the FinnGen cohort (4957 cases and 304,197 controls), and the UK Biobank (9276 cases and 477,069 controls). Colocalization and summary-data-based MR (SMR) analyses were performed sequentially to verify the causal role of candidate proteins. Single cell-type expression analysis, protein-protein interaction (PPI), and druggability evaluation were further conducted to detect the specific cell type with enrichment expression and prioritize potential therapeutic targets. RESULTS Collectively, genetically predicted levels of 13 proteins were associated with CRC risk. Elevated levels of two proteins (GREM1, CHRDL2) and decreased levels of 11 proteins were associated with an increased risk of CRC, among which four (GREM1, CLSTN3, CSF2RA, CD86) were prioritized with the most convincing evidence. These protein-coding genes are mainly expressed in tissue stem cells, epithelial cells, and monocytes in colon tumor tissue. Two interactive pairs of proteins (GREM1 and CHRDL2; MMP2 and TIMP2) were identified to be involved in osteoclast differentiation and tumorigenesis pathways; four proteins (POLR2F, CSF2RA, CD86, MMP2) have been targeted for drug development on autoimmune diseases and other cancers, with the potentials of being repurposed as therapeutic targets for CRC. CONCLUSIONS This study identified several protein biomarkers to be associated with CRC risk and provided new insights into the etiology and promising targets for the development of screening biomarkers and therapeutic drugs for CRC.
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Affiliation(s)
- Jing Sun
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jianhui Zhao
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Fangyuan Jiang
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Lijuan Wang
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK
| | - Qian Xiao
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fengyan Han
- Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jie Chen
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shuai Yuan
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Jingsun Wei
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Susanna C Larsson
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Honghe Zhang
- Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Malcolm G Dunlop
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Colon Cancer Genetics Group, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Susan M Farrington
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Kefeng Ding
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Evropi Theodoratou
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Xue Li
- Department of Big Data in Health Science School of Public Health, and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.
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13
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Jahandideh A, Yarizadeh M, Noei-Khesht Masjedi M, Fatehnejad M, Jahandideh R, Soheili R, Eslami Y, Zokaei M, Ahmadvand A, Ghalamkarpour N, Kumar Pandey R, Nabi Afjadi M, Payandeh Z. Macrophage's role in solid tumors: two edges of a sword. Cancer Cell Int 2023; 23:150. [PMID: 37525217 PMCID: PMC10391843 DOI: 10.1186/s12935-023-02999-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 07/24/2023] [Indexed: 08/02/2023] Open
Abstract
The tumor microenvironment is overwhelmingly dictated by macrophages, intimately affiliated with tumors, exercising pivotal roles in multiple processes, including angiogenesis, extracellular matrix reconfiguration, cellular proliferation, metastasis, and immunosuppression. They further exhibit resilience to chemotherapy and immunotherapy via meticulous checkpoint blockades. When appropriately stimulated, macrophages can morph into a potent bidirectional component of the immune system, engulfing malignant cells and annihilating them with cytotoxic substances, thus rendering them intriguing candidates for therapeutic targets. As myelomonocytic cells relentlessly amass within tumor tissues, macrophages rise as prime contenders for cell therapy upon the development of chimeric antigen receptor effector cells. Given the significant incidence of macrophage infiltration correlated with an unfavorable prognosis and heightened resistance to chemotherapy in solid tumors, we delve into the intricate role of macrophages in cancer propagation and their promising potential in confronting four formidable cancer variants-namely, melanoma, colon, glioma, and breast cancers.
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Affiliation(s)
- Arian Jahandideh
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
- Usern Office, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mahsa Yarizadeh
- Islamic Azad University, Tehran Medical Branch, Tehran, Iran
| | - Maryam Noei-Khesht Masjedi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Fatehnejad
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Romina Jahandideh
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Roben Soheili
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Yeganeh Eslami
- Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Maryam Zokaei
- Department of Food Science and Technology, Faculty of Nutrition Science, Food Science and Technology/National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ardavan Ahmadvand
- Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nogol Ghalamkarpour
- Department of Clinical Laboratory Sciences, School of Allied Medicine, Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Rajan Kumar Pandey
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden
| | - Mohsen Nabi Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden.
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14
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Wang X, Bai Y, Zhou Z, Ye B, Chen Z, Chen X, Wu W. Relationship Between Infiltration of CD163+ TAMs, FoxP3+ Tregs, or CD66b+ TANs and Cell Differentiation in Colorectal Cancer Tissues. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2023; 34:747-752. [PMID: 37232465 PMCID: PMC10441166 DOI: 10.5152/tjg.2023.22064] [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: 02/08/2022] [Accepted: 10/09/2022] [Indexed: 05/27/2023]
Abstract
BACKGROUND/AIMS There are many studies on immune cell infiltration in colorectal cancer, including FoxP3+-regulatory T cells, CD66b+ tumorassociated neutrophils, and CD163+ tumor-associated macrophages. These studies mainly focus on the relationship between cell infiltration and tumor progression, prognosis, and so on, while the relationship between tumor cell differentiation and cell infiltration is poorly understood. We aimed to explore the relationship between cell infiltration and tumor cell differentiation. MATERIALS AND METHODS The tissue microarray and immunohistochemistry were used to determine the infiltration of FoxP3+-regulatory T cells, CD66b+ tumor-associated neutrophils, and CD163+ tumor-associated macrophages in 673 colorectal cancer samples from the Second Affiliated Hospital, Wenzhou Medical University (2001-2009). Kruskal-Wallis test was used to assess the positive cell infiltration in colorectal cancer tissues with tumor cells of varying degrees of differentiation. RESULTS The number of CD163+ tumor-associated macrophages, FoxP3+-regulatory T cells, and CD66b+ tumor-associated neutrophils in colorectal cancer tissues was different, and the level of CD163+ tumor-associated macrophages was the highest while the level of FoxP3+-regulatory T cells was the least. There were significant differences in the cell infiltration of colorectal cancer tissue cells with different levels of differentiation (P < .05). The highest infiltration of CD163+ tumor-associated macrophages (154.07 ± 6.95) and FoxP3+-regulatory T cells (20.14 ± 2.07) were in the poorly differentiated colorectal cancer tissues, while the higher infiltration of CD66b+ tumor-associated neutrophils was in the moderately or well-differentiated colorectal cancer tissues (36.70 ± 1.10 and 36.09 ± 1.06, respectively). CONCLUSION Infiltration of CD163+ tumor-associated macrophages, FoxP3+-regulatory T cells, and CD66b+ tumor-associated neutrophils in colorectal cancer tissues may be related to the differentiation of tumor cells.
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Affiliation(s)
- Xiaobo Wang
- Department of Traumatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Yongyu Bai
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Zhuha Zhou
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Bailiang Ye
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Zhejing Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Xiaolei Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Wenyi Wu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
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15
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Xu G, Mo Y, Li J, Wei Q, Zhou F, Chen J. Two tripartite classification systems of CD86 + and CD206 + macrophages are significantly associated with tumor recurrence in stage II-III colorectal cancer. Front Immunol 2023; 14:1136875. [PMID: 37342343 PMCID: PMC10277500 DOI: 10.3389/fimmu.2023.1136875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 05/22/2023] [Indexed: 06/22/2023] Open
Abstract
Introduction The prognostic value of tumor-associated macrophages remains unclear in colorectal cancer (CRC). Two tripartite classification systems, namely, ratio and quantity subgroups, were investigated as the prognostic stratification tools for stage II-III CRC. Methods We assessed the infiltration intensity of CD86+ and CD206+ macrophages in 449 cases with stage II-III disease by immunohistochemical staining. Ratio subgroups were defined by the lower- and upper-quartile points of CD206+/(CD86++CD206+) macrophage ratio, including the low-, moderate-, and high-ratio subgroups. Quantity subgroups were defined by the median points of CD86+ and CD206+ macrophages and included the low-, moderate-, and high-risk subgroups. The main analysis was recurrence-free survival (RFS) and overall survival (OS). Results Ratio subgroups (RFS/OS: HR=2.677/2.708, all p<0.001) and quantity subgroups (RFS/OS: HR=3.137/3.250, all p<0.001) could serve as independent prognostic indicators that effectively predicted survival outcomes. More importantly, log-rank test revealed that patients in the high-ratio (RFS/OS: HR=2.950/3.151, all p<0.001) or high-risk (RFS/OS: HR=3.453/3.711, all p<0.001) subgroup exhibited decreased survival outcomes after adjuvant chemotherapy. The predictive accuracy of the quantity subgroups within 48 months was higher than that of the ratio subgroups and tumor stage (all p<0.05). Conclusions Ratio and quantity subgroups could serve as independent prognostic indicators that could potentially be incorporated into the tumor staging algorithm to improve prognostic stratification and provide better predictions of survival outcomes in stage II-III CRC after adjuvant chemotherapy.
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Affiliation(s)
- Guozeng Xu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Hubei, China
- Department of Oncology, Liuzhou People’s Hospital of Guangxi Medical University, Guangxi, China
| | - Yuzhen Mo
- Department of Radiation Oncology, Guangzhou Red Cross Hospital of Jinan University, Guangdong, China
| | - Jing Li
- Department of Oncology, Liuzhou People’s Hospital of Guangxi Medical University, Guangxi, China
| | - Qingqing Wei
- Department of Oncology, Liuzhou People’s Hospital of Guangxi Medical University, Guangxi, China
| | - Fuxiang Zhou
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Hubei, China
| | - Jian Chen
- Department of Medical Oncology, Yantai Yuhuangding Hospital of Qingdao University, Shandong, China
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EMR1/ADGRE1 Expression in Cancer Cells Upregulated by Tumor-Associated Macrophages Is Related to Poor Prognosis in Colorectal Cancer. Biomedicines 2022; 10:biomedicines10123121. [PMID: 36551877 PMCID: PMC9775542 DOI: 10.3390/biomedicines10123121] [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: 10/28/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
EMR1, a member of the adhesion G protein-coupled receptor family (ADGRE1), is a macrophage marker that is abnormally expressed in cancer cells. However, its clinical significance in colorectal cancer (CRC) is not well-known. In this investigation, EMR1 expression in tumor cells (EMR1-TC) was found in 91 (22.8%) of the 399 CRC samples tested by immunohistochemical staining and showed a significant relationship with lymph node metastasis. Furthermore, EMR1-TC was significantly associated with CD68+ CD163+ tumor-associated macrophages (TAMs), and CRC with a high combined EMR1-TC+CD68+CD163+ score showed worse recurrence-free survival prognosis. In an in vitro co-culture assay of colon cancer cells with myeloid cells, we found that EMR1 expression significantly upregulated in cancer cells was induced by macrophages. In addition, there was increased expression of M2 markers (CD163 and interleukin-6 & 10) in myeloid portion, while that of M1 markers (CD86 and iNOS) remained unchanged. Accordingly, upon treatment with M2 macrophage polarization inhibitors (O-ATP, trametinib, bardoxolone methyl), EMR1 expression reduced significantly, along with M2 markers (CD163 and interleukin-6 & 10). In conclusion, EMR1-TC was a high-risk factor for lymph node metastasis and correlated with poor recurrence free survival, particularly in patients with TAM-rich CRC. Furthermore, EMR1 expression in colon cancer cells may be related to M2 macrophage polarization and vice versa.
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