Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors

Gastroenterology. 2007 Dec;133(6):1869-81. doi: 10.1053/j.gastro.2007.09.008. Epub 2007 Sep 14.


Background & aims: Chronic inflammation is a risk factor for colon cancer in patients with ulcerative colitis (UC). The molecular mechanisms linking inflammation and colon carcinogenesis are incompletely understood. We tested the hypothesis that Toll-like receptor 4 (TLR4) is involved in tumorigenesis in the setting of chronic inflammation.

Methods: Tissues from UC patients with cancer were examined for TLR4 expression. Colitis-associated neoplasia was induced using azoxymethane injection followed by dextran sodium sulfate treatment in TLR4-deficient or wild-type mice. Inflammation, polyps, and microscopic dysplasia were scored. Cyclooxygenase (Cox)-2 and prostaglandin E(2) production were analyzed by real-time polymerase chain reaction, immunohistochemistry, or enzyme immunoassay. Epidermal growth factor receptor (EGFR) phosphorylation and amphiregulin production were examined by Western blot analysis and enzyme-linked immunosorbent assay, respectively.

Results: We show that TLR4 is overexpressed in human and murine inflammation-associated colorectal neoplasia. TLR4-deficient mice were protected markedly from colon carcinogenesis. Mechanistically, we show that TLR4 is responsible for induction of Cox-2, increased prostaglandin E(2) production, and activation of EGFR signaling in chronic colitis. Amphiregulin, an EGFR ligand, was induced in a TLR4, Cox-2-dependent fashion and contributes to activation of EGFR phosphorylation in colonic epithelial cells.

Conclusions: TLR4 signaling is critical for colon carcinogenesis in chronic colitis. TLR4 activation appears to promote the development of colitis-associated cancer by mechanisms including enhanced Cox-2 expression and increased EGFR signaling. Inhibiting TLR4 signaling may be useful in the prevention or treatment of colitis-associated cancer.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Chronic Disease
  • Colitis / complications
  • Colitis / immunology*
  • Colitis, Ulcerative / complications
  • Colitis, Ulcerative / immunology
  • Colorectal Neoplasms / immunology*
  • Cyclooxygenase 2 / biosynthesis
  • Dinoprostone / biosynthesis
  • Disease Models, Animal
  • Genes, erbB-1 / physiology
  • Humans
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Toll-Like Receptor 4 / biosynthesis
  • Toll-Like Receptor 4 / immunology*
  • Up-Regulation


  • NF-kappa B
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Dinoprostone