Innate immune signaling by toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors

Masayuki Fukata, Yasmin Hernandez, Daisy Conduah, Jason Cohen, Anli Chen, Keith Breglio, Tyralee Goo, David Hsu, Ruliang Xu, Maria T Abreu

Research output: Contribution to journalArticle

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Abstract

Background: Patients with ulcerative colitis are at increased risk for developing colorectal cancer. We have shown that Toll-like receptor-4 (TLR4) is overexpressed in human colitis-associated cancer (CAC) and that mice deficient in TLR4 are markedly protected against colitis-associated neoplasia. We wished to elucidate the specific contributions of TLR4 signaling by myeloid cells and colonic epithelial cells (CEC) in colitis-associated tumorigenesis. Methods: TLR4-deficient mice or wildtype littermates (WT) were transplanted with bone marrow (BM) cells: TLR4-/- BM→WT mice (TLR4-expressing CEC) and WT BM→TLR4-/- mice (TLR4-expressing myeloid cells). Colitis-associated neoplasia was induced by azoxymethane (AOM 7.3 mg/kg) injection and 2 cycles of dextran sodium sulfate (DSS) treatment. Results: The number and size of dysplastic lesions were greater in TLR4-/- BM→WT mice than in WT BM→TLR4-/- mice (P < 0.005). Histologically, TLR4-/- BM→WT mice had greater numbers of mucosal neutrophils and macrophages compared to WT BM→TLR4-/- mice. The chemokines KC and CCL2, important in recruitment of neutrophils and macrophages, respectively, were induced in mice expressing TLR4 in CEC rather than the myeloid compartment. The lamina propria infiltrate of mice expressing TLR4 in CEC was characterized by macrophages expressing Cox-2. Moreover, mice expressing TLR4 in CEC rather than the myeloid compartment had increased production of amphiregulin and EGFR activation. Conclusions: These findings indicate that TLR4 signaling on CEC is necessary for recruitment and activation of Cox-2-expressing macrophages and increasing the number and size of dysplastic lesions. Our results implicate innate immune signaling on CEC as a key regulator of a tumor-promoting microenvironment.

Original languageEnglish
Pages (from-to)997-1006
Number of pages10
JournalInflammatory Bowel Diseases
Volume15
Issue number7
DOIs
StatePublished - Sep 18 2009

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Toll-Like Receptor 4
Colitis
Myeloid Cells
Neoplasms
Epithelial Cells
Macrophages
Azoxymethane
Dextran Sulfate
Tumor Microenvironment
Neutrophil Infiltration
Chemokine CCL2
Ulcerative Colitis
Bone Marrow Cells
Colorectal Neoplasms
Carcinogenesis
Mucous Membrane
Neutrophils

Keywords

  • Colorectal cancer
  • Inflammation
  • Mouse model
  • Toll like receptor
  • Tumor microenvironment

ASJC Scopus subject areas

  • Gastroenterology
  • Immunology and Allergy

Cite this

Innate immune signaling by toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors. / Fukata, Masayuki; Hernandez, Yasmin; Conduah, Daisy; Cohen, Jason; Chen, Anli; Breglio, Keith; Goo, Tyralee; Hsu, David; Xu, Ruliang; Abreu, Maria T.

In: Inflammatory Bowel Diseases, Vol. 15, No. 7, 18.09.2009, p. 997-1006.

Research output: Contribution to journalArticle

Fukata, M, Hernandez, Y, Conduah, D, Cohen, J, Chen, A, Breglio, K, Goo, T, Hsu, D, Xu, R & Abreu, MT 2009, 'Innate immune signaling by toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors', Inflammatory Bowel Diseases, vol. 15, no. 7, pp. 997-1006. https://doi.org/10.1002/ibd.20880
Fukata, Masayuki ; Hernandez, Yasmin ; Conduah, Daisy ; Cohen, Jason ; Chen, Anli ; Breglio, Keith ; Goo, Tyralee ; Hsu, David ; Xu, Ruliang ; Abreu, Maria T. / Innate immune signaling by toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors. In: Inflammatory Bowel Diseases. 2009 ; Vol. 15, No. 7. pp. 997-1006.
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AU - Hernandez, Yasmin

AU - Conduah, Daisy

AU - Cohen, Jason

AU - Chen, Anli

AU - Breglio, Keith

AU - Goo, Tyralee

AU - Hsu, David

AU - Xu, Ruliang

AU - Abreu, Maria T

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AB - Background: Patients with ulcerative colitis are at increased risk for developing colorectal cancer. We have shown that Toll-like receptor-4 (TLR4) is overexpressed in human colitis-associated cancer (CAC) and that mice deficient in TLR4 are markedly protected against colitis-associated neoplasia. We wished to elucidate the specific contributions of TLR4 signaling by myeloid cells and colonic epithelial cells (CEC) in colitis-associated tumorigenesis. Methods: TLR4-deficient mice or wildtype littermates (WT) were transplanted with bone marrow (BM) cells: TLR4-/- BM→WT mice (TLR4-expressing CEC) and WT BM→TLR4-/- mice (TLR4-expressing myeloid cells). Colitis-associated neoplasia was induced by azoxymethane (AOM 7.3 mg/kg) injection and 2 cycles of dextran sodium sulfate (DSS) treatment. Results: The number and size of dysplastic lesions were greater in TLR4-/- BM→WT mice than in WT BM→TLR4-/- mice (P < 0.005). Histologically, TLR4-/- BM→WT mice had greater numbers of mucosal neutrophils and macrophages compared to WT BM→TLR4-/- mice. The chemokines KC and CCL2, important in recruitment of neutrophils and macrophages, respectively, were induced in mice expressing TLR4 in CEC rather than the myeloid compartment. The lamina propria infiltrate of mice expressing TLR4 in CEC was characterized by macrophages expressing Cox-2. Moreover, mice expressing TLR4 in CEC rather than the myeloid compartment had increased production of amphiregulin and EGFR activation. Conclusions: These findings indicate that TLR4 signaling on CEC is necessary for recruitment and activation of Cox-2-expressing macrophages and increasing the number and size of dysplastic lesions. Our results implicate innate immune signaling on CEC as a key regulator of a tumor-promoting microenvironment.

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