Biofilm Epidemiology and Mechanisms in Colon Cancer

 描述（由申请人提供）：结直肠癌（CRC）是美国的公共卫生威胁。由于结肠含有已知最密集的微生物生态系统，因此长期以来一直关注结肠上皮细胞对微生物群的环境暴露如何有助于人类CRC的起始和/或进展。我们在CRC和健康结肠镜检查对照人群中积累的数据表明，结构微生物学和基因组学的组合方法产生了关于微生物群对宿主结肠粘膜影响的新观察结果。也就是说，右（近端）结肠癌（肝曲之前）和远离CRC的配对正常粘膜样品几乎普遍被复杂的细菌生物膜覆盖，这些细菌生物膜表现出细菌侵入所有肿瘤和一些正常结肠组织，而左（远端）CRC和正常组织很少表现出生物膜。在健康的结肠镜检查（非肿瘤）宿主中，只有约10-15%的结肠组织表现出粘膜生物膜，没有地理偏好，表明右半结肠与生物膜形成天然无关。重要的是，生物膜形成与肿瘤和非肿瘤宿主结肠组织中的前致癌途径活化和隐窝细胞增殖相关。因此，我们假设近端结肠容易受到细菌组织的显著变化的影响，这些变化驱动了癌变。我们将使用应用于临床结肠镜检查队列的实验方法来验证我们的假设。我们的具体目标是：1）建立结肠粘膜生物膜发育的自然史;和2）确定生物膜促进结肠癌发生的细菌群落和宿主机制。我们的研究结果将为开发新的预防CRC的工具提供指导。

 DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a public health threat in the United States. Because the colon contains the most densely populated microbial ecosystem known, there has been a longstanding interest in how environmental exposure of colonic epithelial cells to the microbiota contributes to the initiation and/or progression of human CRC. Our data accrued in CRC and healthy colonoscopy control populations reveal that combined approaches, structural microbiology and genomics, yield novel observations regarding the impact of the microbiota on the host colon mucosa. Namely, right (proximal) colon cancers (before the hepatic flexure) and their paired normal mucosal samples far distant from the CRCs are nearly universally covered by complex bacterial biofilms that exhibit bacterial invasion into all tumors and some normal colon tissues whereas left (distal) CRCs and normal tissues infrequently exhibit biofilms. In the healthy colonoscopy (non-tumor) host, only ~10-15% of colon tissues exhibit mucosal biofilms without geographic preference indicating the right colon is not natively associated with biofilm formation. Importantly, biofilm formation correlates with procarcinogenic pathway activation and crypt cell proliferation in tumor and non-tumor host colon tissues. Thus, we hypothesize that the proximal colon is susceptible to marked changes in bacterial organization that drive carcinogenesis. We will test our hypothesis using experimental approaches applied to a clinical colonoscopy cohort. Our specific aims are: 1) to establish the natural history of colon mucosal biofilm development; and 2) to define bacterial community and host mechanisms by which biofilms contribute to colon carcinogenesis. Our results will provide guidance to development of new tools for the prevention of CRC.