TY - JOUR
T1 - Toll-Like Receptor-4 Promotes the Development of Colitis-Associated Colorectal Tumors
AU - Fukata, Masayuki
AU - Chen, Anli
AU - Vamadevan, Arunan S.
AU - Cohen, Jason
AU - Breglio, Keith
AU - Krishnareddy, Suneeta
AU - Hsu, David
AU - Xu, Ruliang
AU - Harpaz, Noam
AU - Dannenberg, Andrew J.
AU - Subbaramaiah, Kotha
AU - Cooper, Harry S.
AU - Itzkowitz, Steven H.
AU - Abreu, Maria T.
N1 - Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2007/12
Y1 - 2007/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=36549082403&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=36549082403&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2007.09.008
DO - 10.1053/j.gastro.2007.09.008
M3 - Article
C2 - 18054559
AN - SCOPUS:36549082403
VL - 133
SP - 1869-1881.e2
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 6
ER -