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Cited by 1,327Cancer Immunotherapy and BiomarkersIL-33, ST2, and ILC PathwaysImmune cells in cancer

Adenoma–linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth

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Grivennikov, Sergei I., Wang, Kepeng, Mucida, Daniel, Stewart, C. Andrew, Schnabl, Bernd, Jauch, Dominik, Taniguchi, Koji, Yu, Guann-Yi +13 more·2012·Nature
DOI 10.1038/nature11465PMC PMC3601659
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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 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
Grivennikov, S. I., Wang, K., Mucida, D., Stewart, C. A., Schnabl, B., Jauch, D., Taniguchi, K., Yu, G.-Y., Österreicher, C. H., Hung, K. E., Datz, C., Feng, Y., Fearon, E. R., Oukka, M., Tessarollo, L., Coppola, V., Yarovinsky, F., Cheroutre, H., Eckmann, L., Trinchieri, G., & Karin, M.
Affiliations
  • University of California San Diego (US)
  • La Jolla Institute for Immunology (US)
  • National Institutes of Health (US)
  • Keio University (JP)
  • University of Vienna (AT)
  • Tufts Medical Center (US)
  • Paracelsus Medical University (AT)
  • University of Michigan (US)
  • Seattle Children's Research Institute (US)
  • The Ohio State University Wexner Medical Center (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
Karin, Michael
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2012-11
Volume
491
Issue
7423
Pages
254-258
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature11465
PMC
PMC3601659
OpenAlex
W2142127071
Cited by
1,327
References
5
Citations by year
2026: 61 · 2025: 65 · 2024: 80 · 2023: 91 · 2022: 96 · 2021: 148 · 2020: 141 · 2019: 100 · 2018: 104 · 2017: 81 · 2016: 91 · 2015: 100 · 2014: 87 · 2013: 75 · 2012: 5
FWCI
42.26
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Amgen
  • Crohn's and Colitis Foundation
  • National Institutes of Health (5r01ai050265-13, 1k99dk088589-01a1)
  • Genentech
  • National Institute on Alcohol Abuse and Alcoholism (R01AA020703)
  • National Cancer Institute (R01CA082223)
  • National Institute of Allergy and Infectious Diseases (R01-AI050265, AI-043477, R01AI043477, R37AI043477)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R24DK080506, DK 080506, K99-DK088589, DK035108, K08DK081830, P01DK035108)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
colorectal cancer, IL-23, IL-17, microbial products, colitis-associated colorectal cancer, APC, β-catenin, tumor growth, tumor microenvironment, Th17 cells, tumour-associated inflammation
MeSH terms
Adenoma, Animals, Bacteria, Cell Division, Cell Transformation, Neoplastic, Colitis, Disease Models, Animal, Humans, Inflammation, Mice, Inbred C57BL, Colorectal Neoplasms, Signal Transduction, Genes, APC, Disease-Free Survival, Interleukin-17, Myeloid Cells, beta Catenin, Toll-Like Receptors, Mice, Myeloid Differentiation Factor 88, Interleukin-23, Tumor Microenvironment

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