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: 10320461
• 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/10320461
• 关键词: Address; Anastomosis - action; Automobile Driving; Bacteria; CT26; Cells; Colon Carcinoma; 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; Knowledge; MMP9 gene; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mentors; Metagenomics; 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; Rectal Cancer; Recurrence; Risk Factors; Role; Sampling; Scientist; Signal Pathway; Signal Transduction; Site; Surgeon; System; Testing; Therapeutic; Time; Tissues; Tumor Cell Biology; Tumor Cell Invasion; 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.

项目总结/摘要 结直肠癌（CRC）是一个主要的健康问题，有近200万新病例被诊断为CRC 2019年全球。虽然手术切除原发性肿瘤可以治愈一些患者，但高达一半的患者 结直肠手术后会复发。中位生存期只有24个月， 几乎所有发生术后复发的患者在当前疗法下将死于其疾病; 因此，迫切需要开发新的策略来理解和预防CRC复发。尽管 越来越多的证据表明，肠道细菌在原发性CRC的发病机制中起着重要作用， 微生物影响CRC复发的发展从未得到解决。 为了解决这一知识差距，Benjamin Shogan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。由于尚不清楚的原因，一个高脂肪的西方人 饮食是原发性和复发性CRC发展的主要危险因素。他发现，当 喂食高脂肪饮食的小鼠进行肠切除术（模仿CRC患者为治愈而进行的手术） 产生胶原酶的生物体，尤其是粪肠球菌优先定殖在 重新连接他发现，E。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，产生富含信号（即uPA，MMP 9， 纤溶酶原）促进肿瘤进展。引人注目的是，当CT 26小鼠癌细胞被 在手术时存在于管腔内（模仿存在于人类患者中的脱落的活肿瘤细胞）， 它们可以通过愈合的肠组织迁移，发展成与人类CRC复发相同的肿瘤， 当小鼠被喂食高脂肪饮食并被胶原分解微生物定殖时。最近的体外实验 发现E.粪肠球菌促进CT 26细胞增强的侵袭和迁移，这表明， CRC复发的交叉点是细菌诱导的肿瘤细胞通过可渗透的肠组织转移。 在这个K 08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， 成为主要研究者，研究肠道微生物组的调节如何提高生存率 结直肠癌患者的结局。在他的导师Ralph Weichselbaum MD和尤金张的指导下， 医学博士，他将测试的假设，即围手术期增殖的胶原溶解有机体的高脂肪饮食 创造了一个肠道微环境，促进癌细胞的腔外迁移， 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 胶原溶解性生物通过其与细胞外基质的相互作用驱动胶原降解的机制。 CT 26细胞的经腔迁移形成腔外肿瘤。这项工作的完成将通知 宿主-微生物-癌细胞之间相互作用，并迫使对新的 预防和治疗结直肠癌的策略。