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

Authors

  • Masayuki Fukata MD, PhD,

    1. Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
    2. Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, New York
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  • Yasmin Hernandez BA,

    1. Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, New York
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  • Daisy Conduah BS,

    1. Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, New York
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  • Jason Cohen MS,

    1. Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, New York
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  • Anli Chen MD,

    1. Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, New York
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  • Keith Breglio MD,

    1. Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, New York
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  • Tyralee Goo MD,

    1. Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, New York
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  • David Hsu MS,

    1. Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, New York
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  • Ruliang Xu MD, PhD,

    1. Department of Pathology, Mount Sinai School of Medicine, New York, New York
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  • Maria T. Abreu MD

    Corresponding author
    1. Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
    2. Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Mount Sinai School of Medicine, New York, New York
    • Division of Gastroenterology, University of Miami Miller School of Medicine, P.O. Box 016960 (D-49), Miami, FL 33101
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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.

(Inflamm Bowel Dis 2009)

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