Role of TLR4 in colitis-associated neoplasia

描述(申请人提供)：炎症性肠病或散发性癌症患者从炎症到不典型增生再到结肠癌的过程仍然知之甚少。研究炎症，特别是先天性免疫信号与结肠癌之间的联系，为发现预防和治疗癌症的新方法提供了可能性。人们怀疑结肠癌的发生与结肠细菌有关。然而，细菌和细菌产品在炎症性肠病致癌中的作用一直很难确定。理解细菌信号在结肠癌发生中的作用的困难之一是，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相关肿瘤发生发展中的独立作用不能得到充分的探讨。目前的建议源于NIDDK赞助的名为：TLR4在急性和慢性小鼠结肠炎发展中的作用的R21所做的工作。在研究TLR4在急性和慢性结肠炎中的作用时，我们发现TLR4对于结肠从粘膜损伤中恢复的能力是必不可少的。缺乏TLR4的动物不会上调COX-2的表达，降低PGE2的产生，并降低肠上皮细胞(IEC)的增殖(Fukata等人)。2006)。上皮修复和癌症是另一种疾病的镜像。目前的建议探索了TLR4在结肠上皮从修复到癌变的转换中可能起重要作用的机制。我们假设通过TLR4的信号与结肠炎相关肿瘤的发生有关。我们发现TLR4在人类CAC中高表达，但不在周围粘膜中表达，支持TLR4在人类疾病中的作用(Fukata等人)。2007)。我们的数据表明，在结肠炎相关肿瘤的小鼠模型中，TLR4-/-小鼠免受异型增生的发展。我们现在发现，在肠道上皮细胞中过表达具有结构性活性的TLR4(Villin-TLR4)会导致致瘤性增加。我们相信，我们的研究结果将允许开发合理的疗法，将阻断TLR4和其他信号通路，如表皮生长因子受体(EGFR)，用于预防或治疗结肠炎相关癌症。公共卫生相关性：炎症在结肠癌的发展过程中很重要。我们已经发现，免疫系统中识别细菌的某种受体TLR4可能与结肠癌的发生有关，特别是在炎症性肠病患者中。在这笔赠款的支持下，我们可以研究TLR4如何促进结肠癌的发展，并试图通过阻断TLR4来预防结肠癌。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Inflammation is important in the development of colon cancer. We have found that a certain receptor of the immune system that recognizes bacteria, TLR4, may be involved in causing colon cancer especially in patients with inflammatory bowel disease. With the support of this grant we can examine how TLR4 contributes to the development of colon cancer and try to prevent colon cancer by blocking TLR4.