Blocking TNF-α in mice reduces colorectal carcinogenesis associated with chronic colitis
Blocking TNF-α in mice reduces colorectal carcinogenesis associated with chronic colitis
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DOI：
10.1172/jc132453
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发表时间：
2008-02-01
影响因子：
15.9
通讯作者：
Mukaida, Naofumi
中科院分区：
文献类型：
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作者：
Popivanova, Boryana K.;Kitamura, Kazuya;Mukaida, Naofumi
炎症性肠病溃疡性结肠炎（UC）常发展为结肠癌。为了了解UC患者发生结肠癌的机制，我们使用了一种疾病的小鼠模型，在该模型中，给药偶氮氧甲烷（AOM），然后重复摄入葡聚糖硫酸钠（DSS），导致严重的结肠炎症和随后的多发性肿瘤发展。我们发现，用AOM和DSS治疗WT小鼠增加了结肠固有层和粘膜下区域的tnf - α表达和表达其主要受体p55 （TNF-Rp55）的浸润性白细胞的数量。随后出现了多个结肠肿瘤。缺乏TNF-Rp55的小鼠经AOM和DSS处理后，粘膜损伤减轻，巨噬细胞和中性粒细胞浸润减少，随后的肿瘤形成减弱。在AOM和DSS治疗后，移植了tnf - rp55缺陷骨髓的WT小鼠的肿瘤发生率也明显低于移植了WT小鼠或tnf - rp55缺陷骨髓的WT小鼠。此外，在AOM和DSS治疗后，WT小鼠给予依那西普（一种tnf - α的特异性拮抗剂）可显著减少肿瘤的数量和大小，并减少中性粒细胞和巨噬细胞的结肠浸润。这些观察结果表明，tnf - α是结肠炎相关结肠癌发生和进展的关键介质，并表明靶向tnf - α可能有助于治疗UC患者的结肠癌。
The inflammatory bowel disease ulcerative colitis (UC) frequently progresses to colon cancer. To understand the mechanisms by which UC patients develop colon carcinomas, we used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. We found that treating WT mice with AOM and DSS increased TNF-alpha expression and the number of infiltrating leukocytes expressing its major receptor, p55 (TNF-Rp55), in the lamina propria and submucosal regions of the colon. This was followed by the development of multiple colonic tumors. Mice lacking TNF-Rp55 and treated with AOM and DSS showed reduced mucosal damage, reduced infiltration of macrophages and neutrophils, and attenuated subsequent tumor formation. WT mice transplanted with TNF-Rp55-deficient bone marrow also developed significantly fewer tumors after AOM and DSS treatment than either WT mice or TNF-Rp55-deficient mice transplanted with WT bone marrow. Furthermore, administration of etanercept, a specific antagonist of TNF-alpha, to WT mice after treatment with AOM and DSS markedly reduced the number and size of tumors and reduced colonic infiltration by neutrophils and macrophages. These observations identify TNF-alpha as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-alpha may be usefull in treating colon cancer in individuals with UC.