Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth

摘要

Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APQ tumour suppressor and activation of β-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses. Curiously, however, 'inflammatory signature' genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates5, referred to as 'tumour-elicited inflammation. Although infiltrating CD4~+ T_H1 cells and CD8~+ cytotoxic T cells constitute a positive prognostic sign in colorectal cancer, myeloid cells and T-helper interleukin (IL)-17-producing (T_H17) cells promote tumorigenesis, and a 'T_H17 expression signature' in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth.%利用一个结肠直肠癌小鼠模型，Sergei rnGrivennikov等人发现，上皮屏障是在早期阶段rn被破坏的，当时肿瘤仍是良性的腺瘤。这种破rn坏导致身体组织被微生物产物穿透，它们会激rn发一个局部炎症反应，涉及由与肿瘤相关的巨rn噬细胞依次生成白介素(IL)-23和IL-17，从而rn促进肿瘤形成。本文作者提供了人体中功能性rn蛋白和粘液素的表达存在缺陷(它表明正常上rn皮屏障被破坏)以及早期和晚期结肠直肠癌病rn灶中IL-23水平升高的证据。因此，上皮屏障rn的消失可以是肠道上皮中基因突变的一个早期rn后果，这能促使形成一个有利于产生肿瘤的炎rn性微环境。