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

Nature. 2012 Nov 8;491(7423):254-8. doi: 10.1038/nature11465.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / genetics
  • Adenoma / immunology
  • Adenoma / microbiology*
  • Adenoma / pathology*
  • Animals
  • Bacteria / metabolism
  • Bacteria / pathogenicity
  • Cell Division
  • Cell Transformation, Neoplastic / pathology*
  • Colitis / complications
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / microbiology*
  • Colorectal Neoplasms / pathology*
  • Disease Models, Animal
  • Disease-Free Survival
  • Genes, APC
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / microbiology
  • Inflammation / pathology
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology*
  • Interleukin-23 / deficiency
  • Interleukin-23 / genetics
  • Interleukin-23 / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Myeloid Differentiation Factor 88 / immunology
  • Myeloid Differentiation Factor 88 / metabolism
  • Signal Transduction
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism
  • Tumor Microenvironment
  • beta Catenin / metabolism

Substances

  • Interleukin-17
  • Interleukin-23
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Toll-Like Receptors
  • beta Catenin