Elucidating the role and mechanisms by which collagenase producing intestinal bacteria promote colorectal cancer recurrence and metastasis following surgery.

项目摘要/摘要 结直肠癌(CRC)是一个主要的健康问题，近200万新的CRC病例被诊断出来 2019年在全球范围内。虽然手术切除原发肿瘤可以治愈一些患者，但多达一半的患者 接受结直肠手术会导致术后复发。中位生存期只有24个月， 用目前的治疗方法，几乎所有术后复发的患者都会死于他们的疾病； 因此，迫切需要制定新的战略，以了解和防止儿童权利委员会的复发。尽管 越来越多的证据表明肠道细菌在原发性结直肠癌的发病机制中起主要作用，肠道如何 微生物对结直肠癌复发的影响一直没有得到解决。 为了解决这一知识差距，本杰明·肖根医学博士开发了令人兴奋的数据，证明了 结直肠癌的复发是一个微生物驱动的过程。由于人们仍然不太清楚的原因，高脂肪的西部 饮食是原发和复发结直肠癌发生的主要危险因素。他发现，当 喂食高脂饮食的小鼠接受肠切除(模仿患者为治愈结直肠癌所做的手术) 胶原酶产生菌，特别是粪肠球菌优先定植于 重新连接。他发现粪肠球菌可以过度激活关键的细胞外基质蛋白水解酶，包括 尿激酶(UPA)-纤溶酶原系统，创造了一个信号丰富的环境(即uPA，MMP9， 纤溶酶原)众所周知，可促进肿瘤进展。值得注意的是，当CT26小鼠癌细胞 在手术时呈现在铝内(模拟存在于人类患者中的剥离的活肿瘤细胞)， 它们可以通过愈合的肠道组织迁移到与人类CRC复发相同的肿瘤中 当小鼠被喂食高脂肪食物并被胶原蛋白分解菌定居时。最近的体外实验已经 发现粪肠球菌促进CT26细胞的侵袭和迁移，这表明在 结直肠癌复发的交集是细菌诱导的肿瘤细胞通过可渗透的肠道组织转移。 在这份K08应用程序中，Shogan博士创建了一个职业发展计划，以实现他的长期目标 成为研究肠道微生物群调节如何提高存活率的首席研究员 结直肠癌患者的预后。在他的导师拉尔夫·魏塞尔鲍姆医学博士和尤金·张的指导下 他将通过高脂饮食来检验这一假说，即围手术期胶原分解菌的增殖。 创造肠道微环境，促进癌细胞腔外迁移，推动结直肠癌 复发。使用体内和体外方法，以及他的人类患者的样本，他将解释 降解胶原蛋白的生物通过与细胞外基质的相互作用，推动 CT26细胞的腔内迁移形成腔外肿瘤。这项工作的完成将通知 宿主-微生物-癌细胞之间的相互作用，迫使小说的彻底反思和发展 预防和治疗结直肠癌的策略。

PROJECT SUMMARY / ABSTRACT Colorectal cancer (CRC) is a major health concern with nearly 2-million new cases of CRC diagnosed worldwide in 2019. While surgical resection of the primary tumor offers a cure for some, up to half of patients undergoing colorectal surgery will develop a postoperative recurrence. With a median survival of only 24 months, almost all patients whom develop a postoperative recurrence will die from their disease with current therapies; there is thus an immediate need to develop new strategies to understand and prevent CRC recurrence. Despite increasing evidence that intestinal bacteria plays a major role in the pathogenesis of primary CRC, how gut microbes influence the development of CRC recurrence has never been addressed. To address this gap in knowledge, Benjamin Shogan MD has developed exciting data demonstrating that CRC recurrence is a microbial driven process. For reasons that remain poorly understood, a high-fat Western diet is the major risk factor for the development of both primary and recurrent CRC. He has discovered that when mice fed a high-fat diet undergo intestinal resection (mimicking the surgery patients undergo for CRC cure) collagenase producing organisms, especially Enterococcus faecalis preferentially colonizes the site of reconnection. He has found that E. faecalis can over-activate critical extracellular matrix proteases, including the urokinase(uPA)-plasminogen system, creating an environment abundant in signals (i.e. uPA, MMP9, plasminogen) well-known to promote tumor progression. Strikingly, when CT26 mouse carcinoma cells are present intraluminally at the time of surgery (mimicking exfoliated viable tumor cells that exist in human patients), they can migrate through healing intestinal tissue to develop tumors identical to human CRC recurrence only when mice are fed a high-fat diet and colonized with collagenolytic organisms. Recent in vitro experiments have found that E. faecalis promotes enhanced invasion and migration of CT26 cells, suggesting that at the intersection of CRC recurrence is bacterial induced metastasis of tumor cells through permeable intestinal tissue. In this K08 application, Dr. Shogan creates a career development plan to acquire his long-term goal of becoming a principal investigator examining how modulation of the intestinal microbiome can improve survival outcomes in patients with CRC. With the guidance of his mentors Ralph Weichselbaum MD and Eugene Chang MD, he will test the hypothesis that the perioperative proliferation of collagenolytic organisms by a high-fat diet creates an intestinal microenvironment that promotes the extraluminal migration of cancer cells, driving CRC recurrence. Using in vivo and in vitro approaches, and samples from his human patients, he will explicate the mechanisms by which collagenolytic organisms, via its interaction with the extracellular matrix, drives the transluminal migration of CT26 cells to form extraluminal tumors. Completion of this work will inform the interaction between host-microbe-cancer cells, and force a complete rethinking and development of novel strategies to prevent and treat colorectal cancer.