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 progresses1,2. Curiously, however, ‘inflammatory signature’ genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer3,4. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates5, referred to as ‘tumour-elicited inflammation’6. Although infiltrating CD4+ TH1 cells and CD8+ cytotoxic T cells constitute a positive prognostic sign in colorectal cancer7,8, myeloid cells and T-helper interleukin (IL)-17-producing (TH17) cells promote tumorigenesis5,6, and a ‘TH17 expression signature’ in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival9. 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 barrier10. 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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Change history
07 November 2012
The FACS image in Fig. 1e was corrected; scale bars in Figs 3b, e and f and 4a, b and f were amended.
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Acknowledgements
We thank eBioscience, GeneTex, Santa Cruz, BioLegend and Cell Signaling for antibodies; Genentech and Amgen for Il23−/− and Il17ra−/− mice, respectively, and S. Reid and E. Southon for the help in generating Il23rF/F mice. This work was supported by Crohn’s and Colitis Foundation of America (Career Development Award number 2693), NIH/National Institute of Diabetes and Digestive and Kidney Diseases (K99-DK088589) and a University of California, San Diego, Digestive Disease Research Development Center Pilot Grant (DK080506) to S.I.G.; Croucher Foundation and China Postdoctoral Science Foundation (20110490919) to K.W.; Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation to K.T.; SPAR Austria to C.D.; NIH (R01CA082223) to E.R.F.; and NIH (AI043477; DK035108) and American Association for Cancer Research (07-60-21-KARI) grants to M.K., who is an American Cancer Society Research Professor. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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S.G. and M.K. conceived the project. S.I.G., K.W., D.M., B.S., D.J., K.T., G.Y.Y., C.O., Y.F. and K.E.H. performed the experiments. S.I.G., K.W., D.M., D.J., H.C., L.E. and M.K. analysed data. C.A.S., V.C., L.T. and G.T. generated Il23rF/F mice. M.O. and F.Y. provided Il23rgfp/gfp and Tlr2,4,9−/− bone marrow, respectively, and Y.F. and E.R.F. provided CPC-APC mice and tissues from Cdx2ERT-Cre-APC mice. C.A.S., E.R.F., H.C. and G.T. provided conceptual advice. C.D. collected and provided human specimens. S.I.G., K.W. and M.K. wrote the manuscript, with all authors contributing to the writing and providing advice.
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This file contains Supplementary Table 1 and Supplementary Figures 1-11. Supplementary Figs 1e, 2b and 8a were corrected on 07 November 2012. (PDF 2192 kb)
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Grivennikov, S., Wang, K., Mucida, D. et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491, 254–258 (2012). https://doi.org/10.1038/nature11465
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DOI: https://doi.org/10.1038/nature11465
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