Role of Bacteria in Colitis-associated Colon Cancer

描述（由申请人提供）：结肠炎相关结肠癌（CAC）是一种主要的癌症形式，也是炎症性肠病（IBD）患者的严重医疗并发症。基于人群的研究表明，溃疡性结肠炎患者30岁时CAC的风险为18%。这两种疾病的共同点是激活了促进炎症、细胞增殖和存活的信号通路。例如，激活转录因子NF-κ B的信号级联促进炎症条件并有利于细胞存活。有趣的是，在IBD的一些实验动物模型（包括IL-10基因缺失的小鼠）中观察到瘤形成。肠腔微生物群落在结肠炎的发展中起关键作用，因此细菌可能参与IL- 10-/-小鼠结肠癌的发展。在初步数据中，我们发现粪肠球菌/大肠杆菌双重相关IL-10-/-小鼠触发肠道炎症并导致结肠发育不良。这表明对肠道细菌的免疫应答失调创造了有利于炎症和发育不良以及癌症发展的条件。肠道中持续的炎症状态可能会诱导遗传和表观遗传事件（甲基化，低乙酰化等），这些事件会使参与控制细胞增殖，生长和存活的基因转录沉默。基于这些结果，我们提出，管腔内细菌引发肠道炎症，然后产生有利于结肠癌发展的环境。以下具体目标旨在检验我们的假设。在AIM I中，确定与肠道细菌相关IL-10-/-小鼠中炎症和致癌相关的信号通路。目的2：研究白细胞介素10（IL-10）-/-小鼠结肠炎相关结肠癌中髓系和肠细胞源性NF-κ B依赖性介质的作用。目的3，建立炎症对大肠杆菌相关IL-10-/-小鼠结肠癌表观遗传学改变和发展的影响。从该项目中获得的信息将有助于制定旨在预防和/或治疗结肠炎相关结肠癌的新策略。基本原理：了解腔细菌对结肠炎相关结肠癌发展的影响将允许设计新的治疗策略来预防/治疗这种病理状况。

DESCRIPTION (provided by applicant): Colitis-associated colon cancer (CAC) represents a major form of cancer and a serious medical complication for patients suffering from inflammatory bowel diseases (IBD). Population-based studies indicate that the risk of CAC among patients with ulcerative colitis is 18% at 30 years. A common denominator for these two conditions is the activation of signaling pathways that promote inflammation, cellular proliferation and survival. For instance, signaling cascades that activate the transcription factor NF-kB promote inflammatory conditions and favor cell survival. Interestingly, neoplasia has been observed in some experimental animal models of IBD including the IL-10 gene deleted mouse. The luminal microflora plays a pivotal role in the development of colitis and consequently bacteria may participate in the development of colon cancer in IL- 10-/- mice. In preliminary data, we found that E.feacalis/E.coli dual associated IL-10-/- mice trigger intestinal inflammation and cause colonic dysplasia. This suggests that dysregulated immune responses to enteric commensal bacteria create conditions favorable to the development of both inflammation and dysplasia and cancer. Persistent inflammatory conditions in the intestine may induce genetic and epigenetic events (methylation, hypoacetylation, ect) that transcriptionally silence genes involved in the control of cellular proliferation, growth and survival. Based on these results, we propose that luminal commensal bacterial trigger intestinal inflammation, which then generate an environment favorable to the development of colon cancer. The following specific aims are designed to test our hypothesis. In AIM I, Identify the signaling pathways associated with inflammation and carcinogenesis in commensal bacteria-associated IL-10-/- mice. AIM 2, Establish the contribution of myeloid and enterocyte-derived NF-kB dependent mediators responsible for commensal bacterial-induced colitis-associated colon cancer in IL-10-/- mice. AIM 3, Establish the impact of inflammation on epigenetic changes and development of colon cancer in commensal bacteria-associated IL-10-/- mice. The information gained from this project will be instrumental for the generation of new strategies aimed at preventing and/or treating colitis-associated colon cancer. Rational in lay term: Understanding the impact of luminal bacteria on the development of colitis-associated colon cancer will allow the design of new therapeutic strategies to prevent/treat this pathological condition.