Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth.
Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth.
复制标题
DOI：
10.1038/nature11465
复制
发表时间：
2012-11-08
期刊：
影响因子：
64.8
通讯作者：
Karin, Michael
中科院分区：
文献类型：
--
作者：
Grivennikov, Sergei I.;Wang, Kepeng;Mucida, Daniel;Stewart, C. Andrew;Schnabl, Bernd;Jauch, Dominik;Taniguchi, Koji;Yu, Guann-Yi;Oesterreicher, Christoph H.;Hung, Kenneth E.;Datz, Christian;Feng, Ying;Fearon, Eric R.;Oukka, Mohamed;Tessarollo, Lino;Coppola, Vincenzo;Yarovinsky, Felix;Cheroutre, Hilde;Eckmann, Lars;Trinchieri, Giorgio;Karin, Michael
大约2%的结直肠癌与预先存在的炎症有关，称为结肠炎相关癌症，但大多数发生在没有潜在炎症性肠病的患者中。结直肠癌通常遵循遗传途径，其中随着肿瘤的出现和进展，腺瘤性结肠息肉病（APC）肿瘤抑制因子的丧失和β-连环蛋白的活化随后是K-Ras、PIK 3CA和TP 53的突变。然而，奇怪的是，结肠炎相关癌症的“炎症特征”基因在结直肠癌中也上调。此外，与大多数实体瘤一样，结肠直肠癌表现出免疫/炎性浸润，称为“肿瘤引起的炎症”。虽然浸润性CD 4 + TH 1细胞和CD 8+细胞毒性T细胞构成了结直肠癌的积极预后标志，但骨髓细胞和辅助性T细胞白细胞介素（IL）-17（TH 17）细胞促进肿瘤发生，并且I/II期结直肠癌中的“TH 17表达特征”与无病生存率的急剧下降相关。尽管其致病的重要性，负责肿瘤引起的炎症的外观的机制知之甚少。许多上皮癌发生在微生物群落附近，微生物群落通过上皮屏障与免疫细胞物理隔离。我们研究了在结肠直肠肿瘤发生的小鼠模型中肿瘤引起的炎症的机制，该模型与人类结肠直肠癌一样，表现出IL-23和IL-17的上调。在这里，我们表明IL-23信号促进肿瘤生长和进展，以及肿瘤IL-17反应的发展。IL-23主要由可能被微生物产物激活的肿瘤相关骨髓细胞产生，微生物产物穿透肿瘤但不穿透邻近组织。早期和晚期结直肠肿瘤都表现出几种屏障蛋白的表达缺陷。我们认为，由结直肠癌引发的遗传病变引起的屏障退化导致微生物产物对腺瘤的侵袭，微生物产物引发肿瘤引发的炎症，进而驱动肿瘤生长。
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 (APC) 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 infiltrates, referred to as ‘tumour elicited inflammation’. Although infiltrating CD4+ TH1 cells and CD8+ cytotoxic T cells constitute a positive prognostic sign in colorectal cancer, myeloid cells and T-helper interleukin (IL)-17-producing (TH17) cells promote tumorigenesis, and a ‘TH17 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.
登录
查看更多内容
影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
影响因子：
4.4
作者：
Ghilardi, N;Kljavin, N;de Sauvage, FJ
通讯作者：
de Sauvage, FJ
影响因子：
6.4
作者：
Newman, JV;Kosaka, T;Schauer, DB
通讯作者：
Schauer, DB
影响因子：
50.3
作者：
Grivennikov S;Karin E;Terzic J;Mucida D;Yu GY;Vallabhapurapu S;Scheller J;Rose-John S;Cheroutre H;Eckmann L;Karin M
通讯作者：
Karin M
影响因子：
30.3
作者：
Ivanov II;Frutos Rde L;Manel N;Yoshinaga K;Rifkin DB;Sartor RB;Finlay BB;Littman DR
通讯作者：
Littman DR