The role of complement in ovarian cancer

补体在卵巢癌中的作用

• 批准号: 6969757
• 负责人: JOHN D LAMBRIS
• 金额: $ 31.3万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6969757
• 关键词: SDS polyacrylamide gel electrophoresis; T lymphocyte; angiogenesis; apoptosis; cell proliferation; complement pathway; complement pathway regulation; cytokine; enzyme linked immunosorbent assay; immunocytochemistry; inflammation; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer blood supply; neoplastic growth; neoplastic process; ovary neoplasms; polymerase chain reaction; western blottings

DESCRIPTION (provided by applicant): The long-term goal of this research is to define the mechanism(s) by which a key component of inflammation, the complement (C') system, influences tumor progression. The relationship between inflammation, innate immunity and cancer is becoming increasingly evident. However, many of the molecular and cellular mechanisms that mediate this relationship remain unresolved. Monocytes recruited into the tumor often provide stimulatory signals that promote, rather than inhibit tumor growth. Angiogenesis, an essential process for wound healing, is crucial for continuous tumor growth and is stimulated by cytokines released from infiltrated inflammatory cells. Despite the obvious link between these processes and the C' system, which has long been recognized to play a major role in mediating local and systemic inflammatory responses, the involvement of C' in cancer is still poorly understood. Preliminary experiments carried out in our laboratory using an in vivo syngeneic model of murine ovarian carcinoma have shown that mice deficient in complement component 3 (C3) display inhibited ovarian tumor growth. Findings from an additional experiment suggested that the observed effect was mediated by the C5a anaphylatoxin, a small cleavage fragment of C5 with potent inflammatory activities. This proposal consists of two aims. The studies in Aim 1 are designed to define the contribution of C' to ovarian cancer and dissect the pathways (s) by which C' may be activated using mice deficient in individual complement components. Aim 2 will focus on dissecting the mechanisms by which the anaphylatoxins C3a and C5a may contribute to tumor growth; the role of other C' components, identified in Aim 1 to be involved in tumor progression, will be studied using similar approaches to those outlined below for the anaphylatoxins. The experiments in Aim 2 will assess the role of the anaphylatoxins in specific processes, such as: i) Tumor angiogenesis, by studying the effects of C3a and C5a on tumor vascularization, cytokine milieu, and recruitment and activation of inflammatory and endothelial cells, ii) Tumor cell proliferation and survival, by examining the role of C3a and C5a as direct or indirect regulators of cell proliferation and apoptosis. iii) Anti-tumor immune responses, by investigating the effects of C3a and C5a on Th1/Th2 lymphocyte balance and anti-tumor T cell responses. This proposal addresses for the first time the involvement of C' as a modulator of the local inflammatory conditions that promote tumor progression. It is designed to dissect critical interactions of C' with the tumor microenvironment and should elucidate the specific role of complement in ovarian carcinogenesis.

描述（由申请人提供）：这项研究的长期目标是定义炎症的关键组成部分，补体（C'）系统影响肿瘤进展的机制。炎症，先天免疫和癌症之间的关系越来越明显。但是，许多介导这种关系的分子和细胞机制仍未解决。招募到肿瘤中的单核细胞通常提供促进的刺激信号，而不是抑制肿瘤生长。血管生成是伤口愈合的基本过程，对于连续肿瘤生长至关重要，并受到浸润性炎症细胞释放的细胞因子的刺激。尽管这些过程与C'系统之间存在明显的联系，而C'系统长期以来一直在介导局部和系统性炎症反应中起着重要作用，但C'在癌症中的参与仍然很少了解。在我们的实验室中使用鼠卵巢癌的体内合同性模型进行的初步实验表明，缺乏补体成分3（C3）的小鼠显示出抑制的卵巢肿瘤生长。另外一个实验的发现表明，观察到的效果是由C5a过敏毒素（C5 A过敏毒素）介导的，C5A过敏毒素是C5的小裂解片段，具有有效的炎症活性。该提议包括两个目标。 AIM 1中的研究旨在定义C'对卵巢癌的贡献，并剖析使用缺乏个体补体成分的小鼠激活C'的途径。 AIM 2将集中于解剖过敏毒素C3A和C5A可能导致肿瘤生长的机制。在AIM 1中确定的其他C'成分的作用将使用与下面概述的过敏毒素相似的方法研究。 AIM 2中的实验将通过研究C3A和C5A对肿瘤血管形成，细胞因子环境，以及炎症细胞的募集和激活，通过研究C3A和C5A对肿瘤血管形成的影响，通过研究C3A和C5A对肿瘤细胞的募集和激活，通过研究肿瘤细胞和肿瘤细胞的生存，C3A和激活的作用，II）通过研究C3A和C5A对肿瘤血管形成，募集和激活C3的作用，II）通过研究C3A和C5A的作用来评估过敏毒素在特定过程中的作用。细胞增殖和凋亡。 iii）抗肿瘤免疫反应，通过研究C3A和C5A对TH1/TH2淋巴细胞平衡和抗肿瘤T细胞反应的影响。该提案首次解决C'作为促进肿瘤进展的局部炎症条件的调节剂的参与。它旨在解剖C'与肿瘤微环境的关键相互作用，并应阐明补体在卵巢癌中的特定作用。