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 journalArticle

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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
JournalGastroenterology
Volume133
Issue number6
DOIs
StatePublished - Dec 1 2007
Externally publishedYes

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Toll-Like Receptor 4
Colitis
Colorectal Neoplasms
Epidermal Growth Factor Receptor
Cyclooxygenase 2
Inflammation
Carcinogenesis
Colon
Ulcerative Colitis
Dinoprostone
Neoplasms
Phosphorylation
Azoxymethane
Dextran Sulfate
Second Primary Neoplasms
Polyps
Immunoenzyme Techniques
Colonic Neoplasms
Real-Time Polymerase Chain Reaction
Western Blotting

ASJC Scopus subject areas

  • Gastroenterology

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Toll-Like Receptor-4 Promotes the Development of Colitis-Associated Colorectal Tumors. / Fukata, Masayuki; Chen, Anli; Vamadevan, Arunan S.; Cohen, Jason; Breglio, Keith; Krishnareddy, Suneeta; Hsu, David; Xu, Ruliang; Harpaz, Noam; Dannenberg, Andrew J.; Subbaramaiah, Kotha; Cooper, Harry S.; Itzkowitz, Steven H.; Abreu, Maria T.

In: Gastroenterology, Vol. 133, No. 6, 01.12.2007.

Research output: Contribution to journalArticle

Fukata, M, Chen, A, Vamadevan, AS, Cohen, J, Breglio, K, Krishnareddy, S, Hsu, D, Xu, R, Harpaz, N, Dannenberg, AJ, Subbaramaiah, K, Cooper, HS, Itzkowitz, SH & Abreu, MT 2007, 'Toll-Like Receptor-4 Promotes the Development of Colitis-Associated Colorectal Tumors', Gastroenterology, vol. 133, no. 6. https://doi.org/10.1053/j.gastro.2007.09.008
Fukata M, Chen A, Vamadevan AS, Cohen J, Breglio K, Krishnareddy S et al. Toll-Like Receptor-4 Promotes the Development of Colitis-Associated Colorectal Tumors. Gastroenterology. 2007 Dec 1;133(6). https://doi.org/10.1053/j.gastro.2007.09.008
Fukata, Masayuki ; Chen, Anli ; Vamadevan, Arunan S. ; Cohen, Jason ; Breglio, Keith ; Krishnareddy, Suneeta ; Hsu, David ; Xu, Ruliang ; Harpaz, Noam ; Dannenberg, Andrew J. ; Subbaramaiah, Kotha ; Cooper, Harry S. ; Itzkowitz, Steven H. ; Abreu, Maria T. / Toll-Like Receptor-4 Promotes the Development of Colitis-Associated Colorectal Tumors. In: Gastroenterology. 2007 ; Vol. 133, No. 6.
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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.",
author = "Masayuki Fukata and Anli Chen and Vamadevan, {Arunan S.} and Jason Cohen and Keith Breglio and Suneeta Krishnareddy and David Hsu and Ruliang Xu and Noam Harpaz and Dannenberg, {Andrew J.} and Kotha Subbaramaiah and Cooper, {Harry S.} and Itzkowitz, {Steven H.} and Abreu, {Maria T}",
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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

PY - 2007/12/1

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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.

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