Abstract
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 H1 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 '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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 254-258 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 491 |
| Issue number | 7423 |
| DOIs | |
| State | Published - Nov 8 2012 |
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Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. / Grivennikov, Sergei I.; Wang, Kepeng; Mucida, Daniel; Stewart, C. Andrew; Schnabl, Bernd; Jauch, Dominik; Taniguchi, Koji; Yu, Guann Yi; Österreicher, 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.
In: Nature, Vol. 491, No. 7423, 08.11.2012, p. 254-258.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth
AU - Grivennikov, Sergei I.
AU - Wang, Kepeng
AU - Mucida, Daniel
AU - Stewart, C. Andrew
AU - Schnabl, Bernd
AU - Jauch, Dominik
AU - Taniguchi, Koji
AU - Yu, Guann Yi
AU - Österreicher, Christoph H.
AU - Hung, Kenneth E.
AU - Datz, Christian
AU - Feng, Ying
AU - Fearon, Eric R.
AU - Oukka, Mohamed
AU - Tessarollo, Lino
AU - Coppola, Vincenzo
AU - Yarovinsky, Felix
AU - Cheroutre, Hilde
AU - Eckmann, Lars
AU - Trinchieri, Giorgio
AU - Karin, Michael
PY - 2012/11/8
Y1 - 2012/11/8
N2 - 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 H1 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 '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.
AB - 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 H1 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 '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.
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U2 - 10.1038/nature11465
DO - 10.1038/nature11465
M3 - Article
VL - 491
SP - 254
EP - 258
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7423
ER -