Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Front Immunol. 2021 May 7;12:669747. doi: 10.3389/fimmu.2021.669747. eCollection 2021.
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 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.
溃疡性结肠炎患者发生结直肠癌的风险增加。虽然炎症相关致癌作用的确切潜在机制尚不清楚，但肠道微生物群和致病菌被认为是炎症和结肠炎相关结肠癌（CAC）的促成因素。在本研究中，我们分析了 TLR4（革兰氏阴性细菌衍生的脂多糖受体）在 CAC 小鼠模型中对肠道炎症和肿瘤发生的影响。在 CAC 发展的炎症阶段，我们观察到结肠组织中表达的强烈上调。在 CAC 的炎症阶段，通过小分子特异性抑制剂阻断 TLR4 信号强烈抑制了结肠肿瘤的发生和进展，与 CAC 对照小鼠相比，浸润的巨噬细胞数量减少，结肠促炎细胞因子水平降低。有趣的是，在 CAC 的炎症阶段通过抗生素治疗抑制细菌信号也能保护小鼠免受严重的肠道炎症，并几乎完全阻止肿瘤生长。然而，抗生素的应用涉及快速和严重的体重减轻，并可能产生不良的副作用。我们的结果表明，细菌在结肠固有免疫细胞上激活 TLR4 会引发炎症并促进肿瘤生长。因此，在肠道炎症期间抑制 TLR4 信号可能是阻止 CAC 发展的一种新方法。
