Fusobacterium nucleatum-mediated stimulation of colorectal cancer: mechanistic studies

简介(申请人提供)：结直肠癌(CRC)是美国第二大癌症死亡原因，长期以来一直被认为是一种遗传性疾病。微生物检测技术的进步彻底改变了我们对许多人类疾病的看法，对结直肠癌的感染病因提出了建议。核梭杆菌(Fn)是一种常见的革兰氏阴性厌氧菌，可通过其独特的FADA粘附素刺激结直肠癌。当前提案的目标是调查国民阵线促进儿童权利公约的机制。FADA通过与E-连环蛋白信号结合刺激大肠癌细胞生长。这种刺激是结直肠癌细胞所特有的，因为FADA能与其他类型的细胞结合 不会刺激细胞生长。我们假设FN与特定的宿主基因突变一起刺激CRC。由于CRC起始于结肠中的癌症干细胞，我们进一步假设FN与特定的启动癌症的干细胞相互作用以促进CRC。为了验证这些假说，我们提出了两个特定的目标：(I)确定FN刺激的结直肠癌发生的宿主和细菌成分；(Ii)研究FN如何在体内刺激结直肠癌的发生。通过这项研究，我们期待获得对结直肠癌发生机制的新见解，并确定预防和治疗结直肠癌的新治疗靶点。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.