| Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. | |
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MedLine Citation:
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PMID: 23034650 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Nature Volume: 491 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-08 Completed Date: 2013-01-10 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 254-8 Citation Subset: IM |
Affiliation:
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Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093-0723, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenoma
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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:
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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; R01CA082223/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Interleukin-17; 0/Interleukin-23; 0/Myd88 protein, mouse; 0/Myeloid Differentiation Factor 88; 0/Toll-Like Receptors; 0/beta Catenin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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