Fusobacterium nucleatum-mediated stimulation of colorectal cancer: mechanistic studies

描述（由申请人提供）：结直肠癌（CRC）是美国癌症死亡的第二大原因，一直被认为是一种遗传病。微生物检测技术的进步已经彻底改变了我们对许多人类疾病的看法，并且已经提出了CRC的感染性病因。具核梭杆菌（Fn）是一种常见的革兰氏阴性口腔厌氧菌，已被证明通过其独特的FadA粘附素刺激CRC。本提案的目标是调查Fn促进CRC的机制。FadA通过结合E-连环蛋白信号刺激CRC细胞生长。这种刺激对结肠直肠癌细胞是特异性的，因为FadA与其他类型的细胞结合， 并不刺激细胞生长。我们假设Fn刺激CRC与特定的宿主基因突变有关。由于CRC起始于结肠中的癌症干细胞，我们进一步假设Fn与特定的癌症起始干细胞相互作用以促进CRC。为了验证这些假设，我们提出了两个具体的目标：（i）确定特定的Fn刺激的结直肠肿瘤发生在体外的主机和细菌组件;（ii）调查Fn如何刺激结直肠肿瘤发生在体内。通过这项研究，我们期望获得对结直肠肿瘤发生机制的新见解，并确定预防和治疗CRC的新治疗靶点。因此，它意味着巨大的翻译潜力。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC), the second leading cause of cancer death in the U.S., has long been recognized as a genetic disease. Advancement in microbial detection technology has revolutionized our view of many human diseases, and infectious etiologies have been suggested for CRC. Fusobacterium nucleatum (Fn), a gram-negative common oral anaerobe, has been shown to stimulate CRC via its unique FadA adhesin. The goal of the current proposal is to investigate the mechanisms by which Fn promotes CRC. FadA stimulates CRC cell growth by binding to E- -catenin signaling. Such stimulation is specific for colorectal carcinoma cells because FadA binding to other types of cells does not stimulate cell growth. We hypothesize that Fn stimulates CRC in conjunction with specific host genetic mutations. Since CRC initiates from cancer stem cells in the colon, we further hypothesize that Fn interacts with specific cancer-initiating stem cells to promote CRC. To test these hypotheses, we propose two specific aims: (i) To determine the host and bacterial components specific for Fn-stimulated colorectal tumorigenesis in vitro; and (ii) to investigate how Fn stimulates colorectal tumorigenesis in vivo. From this study, we anticipate gaining novel insights into the mechanism of colorectal tumorigenesis, and identify novel therapeutic targets for prevention and treatment of CRC. Thus, it implies significant translational potential.