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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.

Author information

Author notes

    • Sergei I. Grivennikov
    •  & Kepeng Wang

    These authors contributed equally to this work.

Affiliations

  1. Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA

    • Sergei I. Grivennikov
    • , Kepeng Wang
    • , Dominik Jauch
    • , Koji Taniguchi
    • , Guann-Yi Yu
    •  & Michael Karin
  2. Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, No. 1120, Lianhua Road, Shenzhen, Guangdong Province, China

    • Kepeng Wang
  3. La Jolla Institute for Allergy and Immunology, La Jolla, California 92093, USA

    • Daniel Mucida
    •  & Hilde Cheroutre
  4. Laboratory of Mucosal Immunology, The Rockefeller University, New York, New York 10065, USA

    • Daniel Mucida
  5. Cancer and Inflammation Program, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702-1201, USA

    • C. Andrew Stewart
    •  & Giorgio Trinchieri
  6. Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA

    • Bernd Schnabl
    • , Christoph H. Österreicher
    •  & Lars Eckmann
  7. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan

    • Koji Taniguchi
  8. Institute of Pharmacology, Center for Physiology and Pharmacology Medical University of Vienna, Vienna, Austria

    • Christoph H. Österreicher
  9. Department of Medicine, Tufts Medical Center, Boston, Massachusetts 02111, USA

    • Kenneth E. Hung
  10. Department of Internal Medicine, Oberndorf Hospital, Paracelsus Medical University, Salzburg, Austria

    • Christian Datz
  11. Departments of Internal Medicine, Human Genetics and Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • Ying Feng
    •  & Eric R. Fearon
  12. Seattle Children’s Research Institute, Seattle, Washington 98105, USA

    • Mohamed Oukka
  13. Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702-1201, USA

    • Lino Tessarollo
  14. Department of Molecular Virology, Immunology & Medical Genetics, Ohio State University Comprehensive Cancer Center, Wexner Medical Center, Columbus, Ohio 43210, USA

    • Vincenzo Coppola
  15. Department of Immunology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA

    • Felix Yarovinsky

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael Karin.

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    Supplementary Information

    This file contains Supplementary Table 1 and Supplementary Figures 1-11. Supplementary Figs 1e, 2b and 8a were corrected on 07 November 2012.

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DOI

https://doi.org/10.1038/nature11465

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