Inhibition of TLR4 Signaling Impedes Tumor Growth in Colitis-Associated Colon Cancer

被引:34
|
作者
Pastille, Eva [1 ]
Fassnacht, Tabea [1 ]
Adamczyk, Alexandra [1 ]
Nhi Ngo Thi Phuong [1 ]
Buer, Jan [1 ]
Westendorf, Astrid M. [1 ]
机构
[1] Univ Duisburg Essen, Univ Hosp Essen, Inst Med Microbiol, Essen, Germany
来源
FRONTIERS IN IMMUNOLOGY | 2021年 / 12卷
关键词
Toll-like receptor 4; colitis-associated colon cancer; inflammation; TAK-242; intestinal immune cells; COLORECTAL-CANCER; GUT MICROBIOTA; TOLL; RECEPTOR-4; RISK;
D O I
10.3389/fimmu.2021.669747
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Patients suffering from ulcerative colitis are at increased risk of developing colorectal cancer. Although the exact underlying mechanisms of inflammation-associated carcinogenesis remain unknown, the intestinal microbiota as well as pathogenic bacteria are discussed as contributors to inflammation and colitis-associated colon cancer (CAC). In the present study, we analyzed the impact of TLR4, the receptor for Gram-negative bacteria derived lipopolysaccharides, on intestinal inflammation and tumorigenesis in a murine model of CAC. During the inflammatory phases of CAC development, we observed a strong upregulation of Tlr4 expression in colonic tissues. Blocking of TLR4 signaling by a small-molecule-specific inhibitor during the inflammatory phases of CAC strongly diminished the development and progression of colonic tumors, which was accompanied by decreased numbers of infiltrating macrophages and reduced colonic pro-inflammatory cytokine levels compared to CAC control mice. Interestingly, inhibiting bacterial signaling by antibiotic treatment during the inflammatory phases of CAC also protected mice from severe intestinal inflammation and almost completely prevented tumor growth. Nevertheless, application of antibiotics involved rapid and severe body weight loss and might have unwanted side effects. Our results indicate that bacterial activation of TLR4 on innate immune cells in the colon triggers inflammation and promotes tumor growth. Thus, the inhibition of the TLR4 signaling during intestinal inflammation might be a novel approach to impede CAC development.
引用
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页数:13
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