Role of TLR4 in colitis-associated neoplasia

从炎症到不典型增生再到结肠癌的过程 炎症性肠病或散发性癌症仍然知之甚少。研究联系 炎症，特别是先天性免疫信号和结肠癌之间的关系提供了 发现预防和治疗癌症的新方法的可能性。结肠菌已经被 被怀疑导致结肠癌的发生。细菌和细菌的贡献 然而，细菌产物在炎症性肠病中的致癌作用一直是困难的。 找出真相。了解细菌信号对结肠的贡献的部分困难 致癌是指结肠炎的发生需要共生细菌。因此， 细菌识别和信号在结肠炎发生中的独立作用 相关的肿瘤不能被充分地探查。 目前的提议源于在NIDDK赞助的 R21题为：TLR4在急性和慢性小鼠结肠炎发展中的作用。在研究 TLR4在急、慢性结肠炎中的作用 从粘膜损伤中恢复的能力。缺乏TLR4的动物不会上调COX-2 表达，损害PGE2的产生，并使肠上皮细胞减少 (IEC)扩散(Fukata等人2006)。上皮修复和癌症是 其他的。目前的提案探讨了TLR4可能在 在结肠上皮中从修复转变为癌变。我们假设信号是 通过TLR4参与结肠炎相关肿瘤的发生发展。我们有 发现TLR4在人CAC中高表达，但在支持a的周围粘膜中不表达 TLR4在人类疾病中的作用(Fukata等人2007)。我们的数据表明TLR4-/-小鼠 在结肠炎相关肿瘤的小鼠模型中保护免受异型增生的发展。 我们现在发现，在肠道上皮细胞中，结构性活性TLR4的过度表达 (Villin-TLR4)导致致瘤性增加。我们相信我们的研究结果将允许 结合阻断TLR4和其他信号转导的合理疗法有待开发 表皮生长因子受体(EGFR)等途径在预防或治疗糖尿病中的作用 结肠炎相关性癌症。

The process leading from inflammation to dysplasia to colon cancer in patients with inflammatory bowel disease or sporadic cancer remains poorly understood. Studying the link between inflammation, in particular, innate immune signaling, and colon cancer offers the possibility to identify novel ways to both prevent and treat cancer. Colonic bacteria have been suspected to contribute to the development of colon cancer. The contribution of bacteria and bacterial products to carcinogenesis in inflammatory bowel disease, however, has been difficult to ferret out. Part of the difficulty in understanding the contribution of bacterial signaling to colon carcinogenesis is that commensal bacteria are required for initiation of colitis. Therefore, the independent contribution of bacterial recognition and signaling in development of colitis- associated neoplasia could not adequately be explored. The current proposal emanates from work performed with the support of a NIDDK-sponsored R21 entitled: Role of TLR4 in development of acute and chronic murine colitis. In studying the role of TLR4 in acute and chronic colitis, we discovered that TLR4 is essential for the colon's ability to recover from mucosal injury. Animals deficient in TLR4 do not upregulate Cox-2 expression, have impaired production of PGE2, and have decreased intestinal epithelial cell (IEC) proliferation (Fukata, et al. 2006). Epithelial repair and cancer are the mirror image of the other. The current proposal explores the mechanism by which TLR4 may be important in the switch from repair to carcinogenesis in the colonic epithelium. We hypothesize that signaling through TLR4 is involved in the development of colitis-associated neoplasia. We have found that TLR4 is overexpressed in human CAC but not the surrounding mucosa supporting a role for TLR4 in human disease (Fukata, et al. 2007). Our data demonstrate that TLR4-/- mice are protected from development of dysplasia in a mouse model of colitis-associated neoplasia. We now show that over-expression of constitutively-active TLR4 in the intestinal epithelium (villin-TLR4) results in increased tumorgenicity. We believe the results of our studies will permit rational therapies to be developed that combine blockade of TLR4 and other signaling pathways, such as epidermal growth factor receptor (EGFR), in the prevention or treatment of colitis associated cancers.