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

被引:1036
作者
Grivennikov, Sergei I. [1 ,2 ]
Wang, Kepeng [1 ,2 ,3 ]
Mucida, Daniel [4 ,5 ]
Stewart, C. Andrew [6 ]
Schnabl, Bernd [7 ]
Jauch, Dominik [1 ,2 ]
Taniguchi, Koji [1 ,2 ,8 ]
Yu, Guann-Yi [1 ,2 ]
Oesterreicher, Christoph H. [7 ,9 ]
Hung, Kenneth E. [10 ]
Datz, Christian [11 ]
Feng, Ying [12 ,13 ,14 ]
Fearon, Eric R. [12 ,13 ,14 ]
Oukka, Mohamed [15 ]
Tessarollo, Lino [16 ]
Coppola, Vincenzo [17 ]
Yarovinsky, Felix [18 ]
Cheroutre, Hilde [4 ]
Eckmann, Lars [7 ]
Trinchieri, Giorgio [6 ]
Karin, Michael [1 ,2 ]
机构
[1] Univ Calif San Diego, Lab Gene Regulat & Signal Transduct, Dept Pharmacol, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Dept Pathol, Sch Med, La Jolla, CA 92093 USA
[3] Shenzhen PKU HKUST Med Ctr, Biomed Res Inst, Shenzhen, Guangdong, Peoples R China
[4] La Jolla Inst Allergy & Immunol, La Jolla, CA 92093 USA
[5] Rockefeller Univ, Lab Mucosal Immunol, New York, NY 10065 USA
[6] NCI, Canc & Inflammat Program, Expt Immunol Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA
[7] Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA
[8] Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo 1608582, Japan
[9] Med Univ Vienna, Ctr Physiol & Pharmacol, Inst Pharmacol, Vienna, Austria
[10] Tufts Med Ctr, Dept Med, Boston, MA 02111 USA
[11] Paracelsus Med Univ, Oberndorf Hosp, Dept Internal Med, Salzburg, Austria
[12] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA
[13] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA
[14] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA
[15] Seattle Childrens Res Inst, Seattle, WA 98105 USA
[16] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21702 USA
[17] Ohio State Univ, Ctr Comprehens Canc, Wexner Med Ctr, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA
[18] Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA
基金
中国博士后科学基金;
关键词
PROMOTES COLON TUMORIGENESIS; COLORECTAL-CANCER; HELPER-CELLS; CUTTING EDGE; MOUSE MODEL; MICE; INFLAMMATION; COLITIS; DIFFERENTIATION; CARCINOGENESIS;
D O I
10.1038/nature11465
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
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 (APC) tumour suppressor and activation of beta-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses(1,2). Curiously, however, 'inflammatory signature' genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer(3,4). Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates(5), referred to as 'tumour-elicited inflammation'(6). Although infiltrating CD4(+) T(H)1 cells and CD8(+) cytotoxic T cells constitute a positive prognostic sign in colorectal cancer(7,8), myeloid cells and T-helper interleukin (IL)-17-producing (T(H)17) cells promote tumorigenesis(5,6), and a 'T(H)17 expression signature' in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival(9). 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(10). 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.
引用
收藏
页码:254 / +
页数:7
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