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

阐明产胶原酶肠道细菌促进结直肠癌术后复发和转移的作用和机制。

• 批准号: 10547761
• 负责人: Benjamin Shogan
• 金额: $ 24.17万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10547761
• 关键词: Address; Anastomosis - action; Automobile Driving; Bacteria; CT26; Cells; Colorectal; Colorectal Cancer; Colorectal Surgery; Data; Development; Development Plans; Diagnosis; Disease; Distal; Enterococcus faecalis; Environment; Excision; Extracellular Matrix; Fatty acid glycerol esters; Funding; Germ-Free; Goals; Health; High Fat Diet; Human; In Vitro; Intervention; Intestinal permeability; Intestines; Invaded; Knowledge; MMP9 gene; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mentors; Metagenomics; Metastasis Induction; Microbe; Modeling; Mus; Neoplasm Metastasis; Oncologist; Operative Surgical Procedures; Organism; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Perioperative; Phenotype; Plasminogen; Play; Postoperative Period; Primary Neoplasm; Principal Investigator; Process; Proliferating; Rectal Cancer; Recurrence; Recurrent Malignant Neoplasm; Risk Factors; Role; Sampling; Scientist; Signal Pathway; Signal Transduction; Site; Surgeon; System; Testing; Therapeutic; Thinking; Time; Tissues; Tumor Cell Biology; Tumor Cell Invasion; Tumor Promotion; Urokinase; Work; bacterial community; cancer cell; cancer diagnosis; cancer recurrence; career; career development; collagenase; colorectal cancer prevention; experimental study; gut microbes; gut microbiome; gut microbiota; healing; improved; improved outcome; in vivo; in vivo evaluation; insight; longitudinal analysis; microbial; migration; neoplastic cell; novel; novel strategies; prevent; survival outcome; tumor; tumor progression; tumorigenesis; western diet

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.

项目概要/摘要 结直肠癌 (CRC) 是一个主要的健康问题，有近 200 万新诊断的结直肠癌病例 2019 年全球范围内。虽然原发肿瘤的手术切除可以治愈一些患者，但多达一半的患者 接受结直肠手术后会出现复发。中位生存期只有24个月， 几乎所有发生术后复发的患者都会因目前的治疗而死于疾病； 因此，迫切需要制定新的策略来了解和预防结直肠癌复发。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发挥着重要作用，肠道细菌如何 微生物对结直肠癌复发发展的影响从未得到解决。 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，表明 CRC 复发是微生物驱动的过程。由于仍知之甚少的原因，高脂肪的西方食品 饮食是原发性和复发性结直肠癌发生的主要危险因素。他发现，当 喂食高脂肪饮食的小鼠接受肠切除术（模仿结直肠癌治愈患者所接受的手术） 产生胶原酶的生物体，尤其是粪肠球菌优先定殖于 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酶，包括 尿激酶 (uPA)-纤溶酶原系统，创造一个富含信号的环境（即 uPA、MMP9、 纤溶酶原）众所周知可促进肿瘤进展。引人注目的是，当 CT26 小鼠癌细胞被 手术时存在于管腔内（模仿人类患者体内存在的脱落的活肿瘤细胞）， 它们可以通过愈合肠道组织迁移，形成与人类结直肠癌复发相同的肿瘤 当小鼠被喂食高脂肪饮食并被胶原蛋白分解生物定植时。最近的体外实验 发现粪肠球菌促进 CT26 细胞的侵袭和迁移增强，这表明在 结直肠癌复发的交叉点是细菌引起的肿瘤细胞通过渗透性肠组织的转移。 在此 K08 申请中，Shogan 博士制定了职业发展计划，以实现他的长期目标： 成为研究肠道微生物组调节如何提高生存率的首席研究员 CRC 患者的结果。在导师 Ralph Weichselbaum MD 和 Eugene Chang 的指导下 医学博士，他将检验以下假设：高脂肪饮食会导致围手术期胶原蛋白溶解微生物的增殖 创造一个肠道微环境，促进癌细胞向腔外迁移，从而推动结直肠癌 复发。他将利用体内和体外方法以及人类患者的样本来解释 胶原蛋白溶解生物体通过与细胞外基质相互作用，驱动 CT26细胞的腔内迁移形成腔外肿瘤。完成这项工作将通知 宿主-微生物-癌细胞之间的相互作用，并迫使人们彻底重新思考和开发新的 预防和治疗结直肠癌的策略。