Metformin changes the immune microenvironment of colorectal cancer in patients with type 2 diabetes mellitus.
Metformin changes the immune microenvironment of colorectal cancer in patients with type 2 diabetes mellitus.
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二甲双胍改变2型糖尿病患者结直肠癌的免疫微环境。
DOI：
10.1111/cas.14615
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发表时间：
2020-11
期刊：
影响因子：
5.7
通讯作者：
Sata N
中科院分区：
文献类型：
--
作者：
Saito A;Kitayama J;Horie H;Koinuma K;Ohzawa H;Yamaguchi H;Kawahira H;Mimura T;Lefor AK;Sata N
越来越多的证据表明，二甲双胍可降低结直肠癌（CRC）的发病率和死亡率。然而，根本的机制尚未完全澄清。本研究的目的是检查接受二甲双胍治疗的2型糖尿病（DM）患者切除的CRC的病理学特征。总共有267例DM患者因I-III期CRC接受了根治性结肠切除术，53例（19.9%）患者接受了药物治疗，包括二甲双胍。二甲双胍治疗患者的病理N分期显著降低（P < .05），无病生存期（DFS）延长（P < .05）。免疫组织化学显示，与未接受二甲双胍治疗的倾向评分匹配病例相比，40例接受二甲双胍治疗的患者浸润性前部区域的CD 3（+）和CD 8（+）肿瘤浸润淋巴细胞（TIL）密度显著较高（P < .05）。二甲双胍治疗患者肿瘤间质中三级淋巴样结构（TLS）的密度显著增加（P < .001）。在这些肿瘤中，有更多的CD 68（+）肿瘤相关巨噬细胞（TAM）浸润（P < .05），而CD 163（+）M2-表型的比例显著降低（P < .001）。二甲双胍摄入倾向于抑制间质纤维化（P = 0.051）。这些结果表明，二甲双胍极大地改变了CRC中浸润免疫细胞的特征，并将肿瘤微环境从免疫抑制状态重新编程为免疫活性状态，这可能导致微观肿瘤扩散的抑制，并改善CRC和2型DM患者的结局。二甲双胍治疗与I-III期结直肠癌和糖尿病患者的淋巴转移减少和无病生存期延长相关。在二甲双胍治疗的结直肠肿瘤中，肿瘤浸润性CD 3（+）和CD 8（+）T细胞和三级淋巴结构的密度显著增加，而CD 163（+）M2型肿瘤相关巨噬细胞的比例降低。二甲双胍可以通过将免疫抑制肿瘤微环境改变为免疫活性状态来抑制肿瘤扩散。
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.
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影响因子：
4
作者：
Li M;Li X;Zhang H;Lu Y
通讯作者：
Lu Y
二甲双胍通过抑制肿瘤相关巨噬细胞的 M2 样极化来预防癌症转移
影响因子：
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影响因子：
3.7
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影响因子：
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作者：
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通讯作者：
Bi C
影响因子：
6.4
作者：
Lee, Jin Ha;Kim, Tae Il;Kim, Won Ho
通讯作者：
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