Role of TLR4 in colitis-associated neoplasia

描述（由申请人提供）：炎症性肠病或散发性癌症患者从炎症到异型增生再到结肠癌的过程仍然知之甚少。研究炎症，特别是先天免疫信号传导与结肠癌之间的联系，可以找到预防和治疗癌症的新方法。结肠细菌被怀疑有助于结肠癌的发展。然而，在炎症性肠病中，细菌和细菌产物对致癌作用的贡献一直难以查明。理解细菌信号对结肠癌发生的贡献的部分困难在于结肠炎的起始需要肠道细菌。因此，无法充分探索细菌识别和信号传导在结肠炎相关瘤形成中的独立贡献。目前的建议源于在NIDDK赞助的R21的支持下进行的工作，该R21题为：TLR 4在急性和慢性小鼠结肠炎发展中的作用。在研究TLR 4在急性和慢性结肠炎中的作用时，我们发现TLR 4对于结肠从粘膜损伤中恢复的能力至关重要。缺乏TLR 4的动物不上调考克斯-2表达，PGE 2的产生受损，并且肠上皮细胞（IEC）增殖减少（Amarata等，2006）。上皮修复和癌症是另一个的镜像。目前的建议探讨了TLR 4可能在结肠上皮从修复到癌变的转变中起重要作用的机制。我们推测通过TLR 4的信号传导参与了结肠炎相关肿瘤的发展。我们已经发现，TLR 4在人CAC中过表达，但在周围粘膜中不过表达，这支持TLR 4在人类疾病中的作用（Amarata，et al.2007）。我们的数据表明，TLR 4-/-小鼠在结肠炎相关瘤形成的小鼠模型中免受发育异常的发展。我们现在表明，组成型活性TLR 4在肠上皮细胞（绒毛-TLR 4）的过度表达导致肿瘤发生性增加。我们相信，我们的研究结果将允许开发合理的疗法，该疗法结合联合收割机阻断TLR 4和其他信号传导途径，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中很重要。我们发现，免疫系统中识别细菌的某种受体TLR 4可能与结肠癌的发生有关，尤其是在炎症性肠病患者中。有了这笔资金的支持，我们可以研究TLR 4如何促进结肠癌的发展，并试图通过阻断TLR 4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.