Toll-Like Receptor-4 Promotes the Development of Colitis-Associated Colorectal Tumors

Masayuki Fukata, Anli Chen, Arunan S. Vamadevan, Jason Cohen, Keith Breglio, Suneeta Krishnareddy, David Hsu, Ruliang Xu, Noam Harpaz, Andrew J. Dannenberg, Kotha Subbaramaiah, Harry S. Cooper, Steven H. Itzkowitz, Maria T. Abreu

Research output: Contribution to journalArticlepeer-review

423 Scopus citations

Abstract

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 E2 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 E2 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.

Original languageEnglish (US)
Pages (from-to)1869-1881.e2
JournalGastroenterology
Volume133
Issue number6
DOIs
StatePublished - Dec 2007

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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