Metformin changes the immune microenvironment of colorectal cancer in patients with type 2 diabetes mellitus
Accumulating evidence suggests that metformin reduces the incidence and mortality of colorectal cancer (CRC). However, underlying mechanisms have not been fully clarified. The aim of this study was to examine the pathological characteristics of resected CRC from patients treated with metformin for t...
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| Vydáno v: | Cancer science Ročník 111; číslo 11; s. 4012 - 4020 |
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| Jazyk: | angličtina |
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John Wiley & Sons, Inc
01.11.2020
John Wiley and Sons Inc |
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| Abstract | Accumulating evidence suggests that metformin reduces the incidence and mortality of colorectal cancer (CRC). However, underlying mechanisms have not been fully clarified. The aim of this study was to examine the pathological characteristics of resected CRC from patients treated with metformin for type 2 diabetes mellitus (DM). In total, 267 patients with DM underwent curative colectomy for Stage I‐III CRC and 53 (19.9%) patients had been treated medically including metformin. Pathological N‐stage was significantly lower in metformin‐treated patients (P < .05) with prolonged disease‐free survival (DFS) (P < .05). Immunohistochemistry showed that the densities of CD3(+) and CD8(+) tumor‐infiltrating lymphocytes (TILs) in the invasive front area were significantly higher in 40 patients treated with metformin compared with propensity score matched cases without metformin (P < .05). The density of tertiary lymphoid structures (TLS) in tumor stroma was markedly increased in metformin‐treated patients (P < .001). In those tumors, there were more CD68(+) tumor‐associated macrophages (TAM) infiltrated (P < .05), while the ratio of CD163(+) M2‐phenotype was markedly reduced (P < .001). Stromal fibrosis tended to be suppressed by metformin intake (P = .051). These findings suggested that metformin drastically changes the characteristics of infiltrating immune cells in CRC and reprograms the tumor microenvironment from immunosuppressive to immunocompetent status, which may lead to suppression of microscopic tumor spread and improve the outcomes of patients with CRC and type 2 DM.
Metformin treatment is associated with fewer lymphatic metastases with prolonged disease‐free survival in patients with stage I‐III colorectal cancer and diabetes mellitus. Densities of tumor‐infiltrating CD3(+) and CD8(+) T cells and tertiary lymphoid structures are significantly increased, while the ratio of CD163(+) M2 type tumor‐associated macrophages is decreased in metformin‐treated colorectal tumor. Metformin may suppress tumor spread by changing the immunosuppressive tumor microenvironment to an immunocompetent status. |
|---|---|
| AbstractList | Accumulating evidence suggests that metformin reduces the incidence and mortality of colorectal cancer (CRC). However, underlying mechanisms have not been fully clarified. The aim of this study was to examine the pathological characteristics of resected CRC from patients treated with metformin for type 2 diabetes mellitus (DM). In total, 267 patients with DM underwent curative colectomy for Stage I‐III CRC and 53 (19.9%) patients had been treated medically including metformin. Pathological N‐stage was significantly lower in metformin‐treated patients (
P
< .05) with prolonged disease‐free survival (DFS) (
P
< .05). Immunohistochemistry showed that the densities of CD3(+) and CD8(+) tumor‐infiltrating lymphocytes (TILs) in the invasive front area were significantly higher in 40 patients treated with metformin compared with propensity score matched cases without metformin (
P
< .05). The density of tertiary lymphoid structures (TLS) in tumor stroma was markedly increased in metformin‐treated patients (
P
< .001). In those tumors, there were more CD68(+) tumor‐associated macrophages (TAM) infiltrated (
P
< .05), while the ratio of CD163(+) M2‐phenotype was markedly reduced (
P
< .001). Stromal fibrosis tended to be suppressed by metformin intake (
P
= .051). These findings suggested that metformin drastically changes the characteristics of infiltrating immune cells in CRC and reprograms the tumor microenvironment from immunosuppressive to immunocompetent status, which may lead to suppression of microscopic tumor spread and improve the outcomes of patients with CRC and type 2 DM. Accumulating evidence suggests that metformin reduces the incidence and mortality of colorectal cancer (CRC). However, underlying mechanisms have not been fully clarified. The aim of this study was to examine the pathological characteristics of resected CRC from patients treated with metformin for type 2 diabetes mellitus (DM). In total, 267 patients with DM underwent curative colectomy for Stage I-III CRC and 53 (19.9%) patients had been treated medically including metformin. Pathological N-stage was significantly lower in metformin-treated patients (P < .05) with prolonged disease-free survival (DFS) (P < .05). Immunohistochemistry showed that the densities of CD3(+) and CD8(+) tumor-infiltrating lymphocytes (TILs) in the invasive front area were significantly higher in 40 patients treated with metformin compared with propensity score matched cases without metformin (P < .05). The density of tertiary lymphoid structures (TLS) in tumor stroma was markedly increased in metformin-treated patients (P < .001). In those tumors, there were more CD68(+) tumor-associated macrophages (TAM) infiltrated (P < .05), while the ratio of CD163(+) M2-phenotype was markedly reduced (P < .001). Stromal fibrosis tended to be suppressed by metformin intake (P = .051). These findings suggested that metformin drastically changes the characteristics of infiltrating immune cells in CRC and reprograms the tumor microenvironment from immunosuppressive to immunocompetent status, which may lead to suppression of microscopic tumor spread and improve the outcomes of patients with CRC and type 2 DM. Accumulating evidence suggests that metformin reduces the incidence and mortality of colorectal cancer (CRC). However, underlying mechanisms have not been fully clarified. The aim of this study was to examine the pathological characteristics of resected CRC from patients treated with metformin for type 2 diabetes mellitus (DM). In total, 267 patients with DM underwent curative colectomy for Stage I‐III CRC and 53 (19.9%) patients had been treated medically including metformin. Pathological N‐stage was significantly lower in metformin‐treated patients (P < .05) with prolonged disease‐free survival (DFS) (P < .05). Immunohistochemistry showed that the densities of CD3(+) and CD8(+) tumor‐infiltrating lymphocytes (TILs) in the invasive front area were significantly higher in 40 patients treated with metformin compared with propensity score matched cases without metformin (P < .05). The density of tertiary lymphoid structures (TLS) in tumor stroma was markedly increased in metformin‐treated patients (P < .001). In those tumors, there were more CD68(+) tumor‐associated macrophages (TAM) infiltrated (P < .05), while the ratio of CD163(+) M2‐phenotype was markedly reduced (P < .001). Stromal fibrosis tended to be suppressed by metformin intake (P = .051). These findings suggested that metformin drastically changes the characteristics of infiltrating immune cells in CRC and reprograms the tumor microenvironment from immunosuppressive to immunocompetent status, which may lead to suppression of microscopic tumor spread and improve the outcomes of patients with CRC and type 2 DM. Accumulating evidence suggests that metformin reduces the incidence and mortality of colorectal cancer (CRC). However, underlying mechanisms have not been fully clarified. The aim of this study was to examine the pathological characteristics of resected CRC from patients treated with metformin for type 2 diabetes mellitus (DM). In total, 267 patients with DM underwent curative colectomy for Stage I-III CRC and 53 (19.9%) patients had been treated medically including metformin. Pathological N-stage was significantly lower in metformin-treated patients (P < .05) with prolonged disease-free survival (DFS) (P < .05). Immunohistochemistry showed that the densities of CD3(+) and CD8(+) tumor-infiltrating lymphocytes (TILs) in the invasive front area were significantly higher in 40 patients treated with metformin compared with propensity score matched cases without metformin (P < .05). The density of tertiary lymphoid structures (TLS) in tumor stroma was markedly increased in metformin-treated patients (P < .001). In those tumors, there were more CD68(+) tumor-associated macrophages (TAM) infiltrated (P < .05), while the ratio of CD163(+) M2-phenotype was markedly reduced (P < .001). Stromal fibrosis tended to be suppressed by metformin intake (P = .051). These findings suggested that metformin drastically changes the characteristics of infiltrating immune cells in CRC and reprograms the tumor microenvironment from immunosuppressive to immunocompetent status, which may lead to suppression of microscopic tumor spread and improve the outcomes of patients with CRC and type 2 DM.Accumulating evidence suggests that metformin reduces the incidence and mortality of colorectal cancer (CRC). However, underlying mechanisms have not been fully clarified. The aim of this study was to examine the pathological characteristics of resected CRC from patients treated with metformin for type 2 diabetes mellitus (DM). In total, 267 patients with DM underwent curative colectomy for Stage I-III CRC and 53 (19.9%) patients had been treated medically including metformin. Pathological N-stage was significantly lower in metformin-treated patients (P < .05) with prolonged disease-free survival (DFS) (P < .05). Immunohistochemistry showed that the densities of CD3(+) and CD8(+) tumor-infiltrating lymphocytes (TILs) in the invasive front area were significantly higher in 40 patients treated with metformin compared with propensity score matched cases without metformin (P < .05). The density of tertiary lymphoid structures (TLS) in tumor stroma was markedly increased in metformin-treated patients (P < .001). In those tumors, there were more CD68(+) tumor-associated macrophages (TAM) infiltrated (P < .05), while the ratio of CD163(+) M2-phenotype was markedly reduced (P < .001). Stromal fibrosis tended to be suppressed by metformin intake (P = .051). These findings suggested that metformin drastically changes the characteristics of infiltrating immune cells in CRC and reprograms the tumor microenvironment from immunosuppressive to immunocompetent status, which may lead to suppression of microscopic tumor spread and improve the outcomes of patients with CRC and type 2 DM. Accumulating evidence suggests that metformin reduces the incidence and mortality of colorectal cancer (CRC). However, underlying mechanisms have not been fully clarified. The aim of this study was to examine the pathological characteristics of resected CRC from patients treated with metformin for type 2 diabetes mellitus (DM). In total, 267 patients with DM underwent curative colectomy for Stage I‐III CRC and 53 (19.9%) patients had been treated medically including metformin. Pathological N‐stage was significantly lower in metformin‐treated patients (P < .05) with prolonged disease‐free survival (DFS) (P < .05). Immunohistochemistry showed that the densities of CD3(+) and CD8(+) tumor‐infiltrating lymphocytes (TILs) in the invasive front area were significantly higher in 40 patients treated with metformin compared with propensity score matched cases without metformin (P < .05). The density of tertiary lymphoid structures (TLS) in tumor stroma was markedly increased in metformin‐treated patients (P < .001). In those tumors, there were more CD68(+) tumor‐associated macrophages (TAM) infiltrated (P < .05), while the ratio of CD163(+) M2‐phenotype was markedly reduced (P < .001). Stromal fibrosis tended to be suppressed by metformin intake (P = .051). These findings suggested that metformin drastically changes the characteristics of infiltrating immune cells in CRC and reprograms the tumor microenvironment from immunosuppressive to immunocompetent status, which may lead to suppression of microscopic tumor spread and improve the outcomes of patients with CRC and type 2 DM. Metformin treatment is associated with fewer lymphatic metastases with prolonged disease‐free survival in patients with stage I‐III colorectal cancer and diabetes mellitus. Densities of tumor‐infiltrating CD3(+) and CD8(+) T cells and tertiary lymphoid structures are significantly increased, while the ratio of CD163(+) M2 type tumor‐associated macrophages is decreased in metformin‐treated colorectal tumor. Metformin may suppress tumor spread by changing the immunosuppressive tumor microenvironment to an immunocompetent status. Accumulating evidence suggests that metformin reduces the incidence and mortality of colorectal cancer (CRC). However, underlying mechanisms have not been fully clarified. The aim of this study was to examine the pathological characteristics of resected CRC from patients treated with metformin for type 2 diabetes mellitus (DM). In total, 267 patients with DM underwent curative colectomy for Stage I‐III CRC and 53 (19.9%) patients had been treated medically including metformin. Pathological N‐stage was significantly lower in metformin‐treated patients (P < .05) with prolonged disease‐free survival (DFS) (P < .05). Immunohistochemistry showed that the densities of CD3(+) and CD8(+) tumor‐infiltrating lymphocytes (TILs) in the invasive front area were significantly higher in 40 patients treated with metformin compared with propensity score matched cases without metformin (P < .05). The density of tertiary lymphoid structures (TLS) in tumor stroma was markedly increased in metformin‐treated patients (P < .001). In those tumors, there were more CD68(+) tumor‐associated macrophages (TAM) infiltrated (P < .05), while the ratio of CD163(+) M2‐phenotype was markedly reduced (P < .001). Stromal fibrosis tended to be suppressed by metformin intake (P = .051). These findings suggested that metformin drastically changes the characteristics of infiltrating immune cells in CRC and reprograms the tumor microenvironment from immunosuppressive to immunocompetent status, which may lead to suppression of microscopic tumor spread and improve the outcomes of patients with CRC and type 2 DM. Metformin treatment is associated with fewer lymphatic metastases with prolonged disease‐free survival in patients with stage I‐III colorectal cancer and diabetes mellitus. Densities of tumor‐infiltrating CD3(+) and CD8(+) T cells and tertiary lymphoid structures are significantly increased, while the ratio of CD163(+) M2 type tumor‐associated macrophages is decreased in metformin‐treated colorectal tumor. Metformin may suppress tumor spread by changing the immunosuppressive tumor microenvironment to an immunocompetent status. |
| Author | Saito, Akira Koinuma, Koji Kitayama, Joji Kawahira, Hiroshi Lefor, Alan Kawarai Yamaguchi, Hironori Sata, Naohiro Ohzawa, Hideyuki Horie, Hisanaga Mimura, Toshiki |
| AuthorAffiliation | 2 Department of Clinical Oncology Jichi Medical University Shimotsuke Japan 1 Department of Gastrointestinal Surgery Jichi Medical University Shimotsuke Japan |
| AuthorAffiliation_xml | – name: 1 Department of Gastrointestinal Surgery Jichi Medical University Shimotsuke Japan – name: 2 Department of Clinical Oncology Jichi Medical University Shimotsuke Japan |
| Author_xml | – sequence: 1 givenname: Akira surname: Saito fullname: Saito, Akira organization: Jichi Medical University – sequence: 2 givenname: Joji orcidid: 0000-0002-5708-7130 surname: Kitayama fullname: Kitayama, Joji email: kitayama@jichi.ac.jp organization: Jichi Medical University – sequence: 3 givenname: Hisanaga surname: Horie fullname: Horie, Hisanaga organization: Jichi Medical University – sequence: 4 givenname: Koji surname: Koinuma fullname: Koinuma, Koji organization: Jichi Medical University – sequence: 5 givenname: Hideyuki surname: Ohzawa fullname: Ohzawa, Hideyuki organization: Jichi Medical University – sequence: 6 givenname: Hironori surname: Yamaguchi fullname: Yamaguchi, Hironori organization: Jichi Medical University – sequence: 7 givenname: Hiroshi surname: Kawahira fullname: Kawahira, Hiroshi organization: Jichi Medical University – sequence: 8 givenname: Toshiki surname: Mimura fullname: Mimura, Toshiki organization: Jichi Medical University – sequence: 9 givenname: Alan Kawarai surname: Lefor fullname: Lefor, Alan Kawarai organization: Jichi Medical University – sequence: 10 givenname: Naohiro surname: Sata fullname: Sata, Naohiro organization: Jichi Medical University |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32794612$$D View this record in MEDLINE/PubMed |
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| Copyright | 2020 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. 2020. This work is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. |
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| Publisher | John Wiley & Sons, Inc John Wiley and Sons Inc |
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| SubjectTerms | Adult Aged Aged, 80 and over Antibodies CD163 antigen CD3 antigen CD8 antigen Cloning Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - complications Colorectal Neoplasms - immunology Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology Diabetes Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - complications Diabetes Mellitus, Type 2 - immunology Diabetes Mellitus, Type 2 - metabolism Female Fibrosis Gender Hemoglobin Humans Hypoglycemic Agents - pharmacology Immunohistochemistry Insulin Invasiveness Lymphocytes Lymphocytes, Tumor-Infiltrating - immunology Lymphocytes, Tumor-Infiltrating - metabolism Lymphocytes, Tumor-Infiltrating - pathology Macrophages Male Metastasis Metformin Metformin - pharmacology Middle Aged Mortality Neoplasm Metastasis Neoplasm Staging Original Phenotypes Regression analysis Stroma Surgery tertiary lymphoid structure Tumor Microenvironment - drug effects Tumor Microenvironment - immunology Tumor-Associated Macrophages - drug effects Tumor-Associated Macrophages - immunology Tumor-Associated Macrophages - metabolism Tumors tumor‐associated macrophage tumor‐infiltrating lymphocytes |
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| Title | Metformin changes the immune microenvironment of colorectal cancer in patients with type 2 diabetes mellitus |
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