Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors.
OBJECTIVE
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.
Fukata
Masayuki
M
Inflammatory Bowel Disease Center, Mount Sinai School of Medicine, New York, New York, USA.
Chen
Anli
A
Vamadevan
Arunan S
AS
Cohen
Jason
J
Breglio
Keith
K
Krishnareddy
Suneeta
S
Hsu
David
D
Xu
Ruliang
R
Harpaz
Noam
N
Dannenberg
Andrew J
AJ
Subbaramaiah
Kotha
K
Cooper
Harry S
HS
Itzkowitz
Steven H
SH
Abreu
Maria T
MT
D000818:Animals; D002460:Cell Line; D002908:Chronic Disease; D003092:Colitis / Q000150:complications / Q000276:immunology*; D003093:Colitis, Ulcerative / Q000150:complications / Q000276:immunology; D015179:Colorectal Neoplasms / Q000276:immunology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D004195:Disease Models, Animal; D018773:Genes, erbB-1 / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000276:immunology*; D015854:Up-Regulation
D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone