Document Detail


Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth.
MedLine Citation:
PMID:  23034650     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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(+) T(H)1 cells and CD8(+) cytotoxic T cells constitute a positive prognostic sign in colorectal cancer, myeloid cells and T-helper interleukin (IL)-17-producing (T(H)17) cells promote tumorigenesis, and a 'T(H)17 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.
Authors:
Sergei I Grivennikov; Kepeng Wang; Daniel Mucida; C Andrew Stewart; Bernd Schnabl; Dominik Jauch; Koji Taniguchi; Guann-Yi Yu; Christoph H Osterreicher; Kenneth E Hung; Christian Datz; Ying Feng; Eric R Fearon; Mohamed Oukka; Lino Tessarollo; Vincenzo Coppola; Felix Yarovinsky; Hilde Cheroutre; Lars Eckmann; Giorgio Trinchieri; Michael Karin
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Nature     Volume:  491     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-08     Completed Date:  2013-01-10     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  254-8     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenoma / genetics,  immunology,  microbiology*,  pathology*
Animals
Bacteria / metabolism,  pathogenicity
Cell Division
Cell Transformation, Neoplastic / pathology*
Colitis / complications
Colorectal Neoplasms / genetics,  immunology,  microbiology*,  pathology*
Disease Models, Animal
Disease-Free Survival
Genes, APC
Humans
Inflammation / genetics,  immunology,  microbiology,  pathology
Interleukin-17 / genetics,  immunology*
Interleukin-23 / deficiency,  genetics,  immunology*
Mice
Mice, Inbred C57BL
Myeloid Cells / immunology,  metabolism
Myeloid Differentiation Factor 88 / immunology,  metabolism
Signal Transduction
Toll-Like Receptors / immunology,  metabolism
Tumor Microenvironment
beta Catenin / metabolism
Grant Support
ID/Acronym/Agency:
AI043477/AI/NIAID NIH HHS; DK035108/DK/NIDDK NIH HHS; DK080506/DK/NIDDK NIH HHS; K08 DK081830/DK/NIDDK NIH HHS; K99 DK088589/DK/NIDDK NIH HHS; K99-DK088589/DK/NIDDK NIH HHS; R01 AA020703/AA/NIAAA NIH HHS; R01 AI043477/AI/NIAID NIH HHS; R01 AI050265/AI/NIAID NIH HHS; R01 CA082223/CA/NCI NIH HHS; R01CA082223/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Interleukin-17; 0/Interleukin-23; 0/Myd88 protein, mouse; 0/Myeloid Differentiation Factor 88; 0/Toll-Like Receptors; 0/beta Catenin
Comments/Corrections

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