Surgery triggered immune response and liver metastases

项目摘要 结直肠癌是一个毁灭性的死亡原因在世界范围内，与大多数患者死亡的结果 肝转移在可行的情况下，切除肝转移瘤可改善总体和疾病- 但是，50-60%的患者在手术切除后会出现肝复发， 治疗失败的主要原因。手术引起的炎症一直被认为会增加风险 肿瘤复发;然而，确切的机制仍然知之甚少。激活免疫 手术后的反应是修复过程的基础，但有证据表明， 炎症反应也可能引起肿瘤环境的改变，从而促进疾病复发 和全身转移。该提案侧重于有助于手术的关键因素和机制- 诱导转移形成。我们的实验室先前揭示了一个新的发现，即中性粒细胞， 在对手术的免疫反应中的主要细胞，可以在手术后形成中性粒细胞胞外陷阱（NETs 靶向NET可以减轻肝脏的应激;并且，靶向NET可以改善小鼠的肝脏以及全身炎症。在 此外，我们最新的令人兴奋的结果表明，增加NET形成后，手术应力的 肝脏促进了转移性结直肠疾病的发展和进展。 因此，这项拨款建议的整体目的，是要确定在 肝脏手术应激后，促进循环肿瘤细胞的侵袭和现有肿瘤细胞的生长， 微转移性疾病，以促进疾病进展。我们还将在临床上验证这些机制 接受肝脏手术治疗转移性结直肠癌患者的结局。在目标1中，我们将确定 NET在捕获手术期间释放的循环肿瘤细胞中的作用。目标2将确定手术的作用 诱导NET维持促炎微环境以促进转移性生长。的焦点 目的3：探讨线粒体生物合成在NET介导的肝内肝损伤过程中的作用。 肿瘤进展。这些研究将大大提高我们对炎症途径的认识， 癌症相关手术后发生的机械变化，两者都是发展的关键， 新的治疗策略，以防止肿瘤复发，并随后降低发病率和死亡率， 各种临床环境。

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.