Surgery triggered immune response and liver metastases

手术引发免疫反应和肝转移

• 批准号: 10333299
• 负责人: Allan Tsung
• 金额: --
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-06-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10333299
• 关键词: Acceleration; Applications Grants; Biogenesis; Blood Platelets; Cell Line; Cells; Clinical; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Curative Surgery; Cytokine Network Pathway; Deposition; Development; Disease; Disease Progression; Disease-Free Survival; Environment; Excision; Goals; Growth; Hepatic; Host Defense Mechanism; Immune response; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-17; Internet; Ischemia; Knowledge; Laboratories; Lead; Link; Liver; Liver diseases; Malignant Neoplasms; Mediating; Metabolic; Metastatic Neoplasm to the Liver; Microscopic; Mitochondria; Morbidity - disease rate; Motion; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Oxidative Phosphorylation; Pathway interactions; Patient-Focused Outcomes; Patients; Perioperative; Play; Primary Neoplasm; Process; Recurrence; Reperfusion Therapy; Risk; Role; Site; Stress; Structure; Time; Tissues; Treatment Failure; Tumor stage; Work; cancer cell; cell growth; disorder later incidence prevention; experience; extracellular; immune activation; improved; inflammatory milieu; intrahepatic; intrahepatic cancer; metastatic colorectal; microbial; mortality; neoplastic cell; neutrophil; novel; novel therapeutic intervention; pathogen; prevent; reparative process; response; systemic inflammatory response; tumor; tumor growth; tumor progression; tumorigenic

PROJECT SUMMARY Colorectal cancer is a devastating cause of mortality worldwide, with the majority of patients dying as a result of hepatic metastasis. When feasible, resection of hepatic metastases provides improved overall and disease- free survival; however, hepatic recurrence after surgical resection occurs in 50-60% of patients and is the major cause of treatment failure. Surgery-induced inflammation has long been suggested to enhance the risk of tumor recurrence; however the exact mechanisms remain poorly understood. Activation of the immune response following surgery is fundamental for reparative processes but evidence suggests that the inflammatory response may also evoke alternations in the tumor environment to promote disease recurrence and systemic metastases. This proposal focuses on key factors and mechanisms that contribute to surgery- induced metastasis formation. Our laboratory previously revealed the novel finding that neutrophils, the principal cells in the immune response to surgery, can form neutrophil extracellular traps (NETs) after surgical stress to the liver; and, targeting NETs ameliorates the hepatic as well as systemic inflammation in mice. In addition, our latest exciting results demonstrate that increased NET formation following surgical stress of the liver advances the acceleration of both the development and progression of metastatic colorectal disease. Thus, the overall objective of this grant proposal is to determine the mechanisms by which NETs, formed in the liver following surgical stress, promote the invasiveness of circulating tumor cells and the growth of existing micro-metastatic disease to facilitate disease progression. We will also validate these mechanisms in clinical outcomes of patients undergoing liver surgery for metastatic colorectal cancer. In Aim 1, we will determine the role of NETs in capturing circulating tumor cells released during surgery. Aim 2 will identify the role of surgery induced NETs in maintaining a pro-inflammatory microenvironment to promote metastatic growth. The focus of Aim 3 will be to establish the role of mitochondrial biogenesis in the process of NET-mediated intrahepatic tumor progression. These studies will greatly enhance our knowledge of the inflammatory pathways and mechanistic changes that occur after cancer related surgery, both of which are pivotal for the development of new therapeutic strategies to prevent tumor recurrence, and subsequently decrease morbidity and mortality, in a variety of clinical settings.

项目摘要 结直肠癌是全球死亡率的毁灭性原因，因此大多数患者死亡 肝转移。当可行时，肝转移的切除提供了改善的整体和疾病 - 自由生存；但是，手术切除后的肝复发发生在50-60％的患者中，是 治疗失败的主要原因。长期以外，已经提出了手术引起的炎症以提高风险 肿瘤复发；但是，确切的机制仍然很少理解。免疫的激活 手术后的反应对于修复过程至关重要，但有证据表明 炎症反应也可能引起肿瘤环境中的交替以促进疾病复发 和全身转移。该提案的重点是有助于手术的关键因素和机制 - 诱导的转移形成。我们的实验室以前揭示了中性粒细胞的新发现，即 免疫反应中的主要细胞可以在手术后形成中性粒细胞外陷阱（NET） 压力肝脏；并且，靶向网可以改善小鼠的肝和全身性炎症。在 此外，我们最新的令人兴奋的结果表明，在手术应力后，净形成增加了 肝脏可以加速转移性结直肠疾病的发展和发展。 因此，该赠款提案的总体目的是确定在该机制中形成的机制 手术应激后的肝脏，促进循环肿瘤细胞的侵入性和现有的生长 微转移性疾病以促进疾病进展。我们还将在临床中验证这些机制 接受转移性结直肠癌的肝脏手术的患者的结局。在AIM 1中，我们将确定 网络在手术期间释放的循环肿瘤细胞中的作用。 AIM 2将确定手术的作用 诱导的网保持促炎性微环境以促进转移性生长。重点 AIM 3将是确定线粒体生物发生在网络介导的肝内的作用 肿瘤进展。这些研究将大大增强我们对炎症途径的了解和 与癌症相关手术后发生的机械变化，这两者都是关键的发展 预防肿瘤复发并随后降低发病率和死亡率的新的治疗策略 各种临床环境。