IL17产生的先天性和适应性冗余来源驱动结肠癌发生。

Redundant Innate and Adaptive Sources of IL17 Production Drive Colon Tumorigenesis.

作者信息

Housseau Franck, Wu Shaoguang, Wick Elizabeth C, Fan Hongni, Wu Xinqun, Llosa Nicolas J, Smith Kellie N, Tam Ada, Ganguly Sudipto, Wanyiri Jane W, Iyadorai Thevambiga, Malik Ausama A, Roslani April C, Vadivelu Jamunarani S, Van Meerbeke Sara, Huso David L, Pardoll Drew M, Sears Cynthia L

机构信息

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

出版信息

Cancer Res. 2016 Apr 15;76(8):2115-24. doi: 10.1158/0008-5472.CAN-15-0749. Epub 2016 Feb 15.

Abstract

IL17-producing Th17 cells, generated through a STAT3-dependent mechanism, have been shown to promote carcinogenesis in many systems, including microbe-driven colon cancer. Additional sources of IL17, such as γδ T cells, become available under inflammatory conditions, but their contributions to cancer development are unclear. In this study, we modeled Th17-driven colon tumorigenesis by colonizing Min(Ap) (c+/-) mice with the human gut bacterium, enterotoxigenic Bacteroides fragilis (ETBF), to investigate the link between inflammation and colorectal cancer. We found that ablating Th17 cells by knocking out Stat3 in CD4(+) T cells delayed tumorigenesis, but failed to suppress the eventual formation of colonic tumors. However, IL17 blockade significantly attenuated tumor formation, indicating a critical requirement for IL17 in tumorigenesis, but from a source other than Th17 cells. Notably, genetic ablation of γδ T cells in ETBF-colonized Th17-deficient Min mice prevented the late emergence of colonic tumors. Taken together, these findings support a redundant role for adaptive Th17 cell- and innate γδT17 cell-derived IL17 in bacteria-induced colon carcinogenesis, stressing the importance of therapeutically targeting the cytokine itself rather than its cellular sources. Cancer Res; 76(8); 2115-24. ©2016 AACR.

摘要

通过一种依赖 STAT3 的机制产生的分泌白细胞介素 17(IL17)的辅助性 T 细胞 17(Th17 细胞)已被证明在包括微生物驱动的结肠癌在内的许多系统中促进肿瘤发生。IL17 的其他来源,如 γδT 细胞,在炎症条件下会出现,但其对癌症发展的作用尚不清楚。在本研究中,我们通过用人肠道细菌产肠毒素脆弱拟杆菌(ETBF)定殖 Min(Ap)(c+/-)小鼠来模拟 Th17 驱动的结肠肿瘤发生,以研究炎症与结直肠癌之间的联系。我们发现,通过敲除 CD4(+)T 细胞中的 Stat3 来消除 Th17 细胞可延迟肿瘤发生,但未能抑制结肠肿瘤的最终形成。然而,IL17 阻断显著减弱了肿瘤形成,表明肿瘤发生过程中对 IL17 有关键需求,但来源不是 Th17 细胞。值得注意的是,在 ETBF 定殖的 Th17 缺陷型 Min 小鼠中对 γδT 细胞进行基因敲除可防止结肠肿瘤的后期出现。综上所述,这些发现支持适应性 Th17 细胞和先天性 γδT17 细胞来源的 IL17 在细菌诱导的结肠癌发生中具有冗余作用,强调了在治疗上靶向细胞因子本身而非其细胞来源的重要性。《癌症研究》;76(8);2115 - 24。©2016 美国癌症研究协会。

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