Complement in cancer establishment and growth

这项研究的长期目标是确定炎症的一个关键组成部分， 补体（C1）系统影响肿瘤的形成和发展。的关系 炎症，先天免疫和癌症变得越来越明显。尽管有明显的联系， 尽管C'系统与炎症有关，但C'在癌症中的参与仍然知之甚少。前期工作从 我们的实验室表明补体成分在上皮性卵巢癌中局部表达。 此外，使用同基因小鼠卵巢癌移植模型，我们已经表明，肿瘤 生长依赖于C'激活，如补体成分3（C3）的遗传缺失或药理学抑制 C5 a过敏毒素是C5的一种小裂解片段，具有强烈的炎症活性，阻碍了肿瘤的生长。 增长我们假设大量的C'激活发生在肿瘤中，这是由肿瘤利用， 通过（i）激活血管生成和（ii）直接作用于肿瘤细胞来建立自身并生长， 其可能部分由C ′组分和/或C ′-活化的细胞因子网络介导。这项建议 包括三个目标。目标1中的研究旨在确定补体在癌症中的作用 建立和发展。我们将分析补体抑制对肿瘤形成的影响， 通过遗传方法取得进展。我们将使用MISIR-TAg，一种卵巢癌转基因小鼠模型， 在MISIIR-TAg小鼠中，以100%的表型转移率检测癌症，并在MISIIR-TAg小鼠中检测癌症表型， 具有不同程度的C'缺乏（C3“”、C5“”、C3 aR“”或CSaR“”）的背景。这些研究报告将 辅以补体激活的药理学抑制或补体的拮抗作用 过敏毒素目的2将研究补体在肿瘤血管形成中的作用。我们将研究 在C'充足的小鼠中、在C'组分缺乏的小鼠中和在C '缺乏的小鼠中的自体和移植肿瘤中， 用C'拮抗剂治疗，并定量C'缺失或拮抗作用对肿瘤血管形成的影响。在 此外，我们将研究C '，特别是C3 a和C5 a过敏毒素在肿瘤血管形成中的作用 通过募集造血干细胞、骨髓内皮祖细胞和髓系细胞， 内皮前体目的3将研究补体在调节肿瘤细胞死亡和 增殖我们将确定C3 a过敏毒素促进炎症激活、增殖 和卵巢癌细胞的体外存活。该提案首先针对 C'作为促进肿瘤建立的局部炎症条件的调节剂的参与时间 和/或进展。它将与项目1互动，以了解补体激活如何影响炎症 网络和细胞存活和增殖在正常再生，免疫病理修复和 异常的癌症生长它将与项目3相互作用，以测试靶向药物化合物的效果。 补体级联对癌症发展和进展的影响。

The long-term goal of this research is to define the mechanism(s) by which a key component of inflammation, the complement (C1) system, influences tumor establishment and progression. The relationship between inflammation, innate immunity and cancer is becoming increasingly evident. Despite the obvious link between inflammation and the C' system, the involvement of C' in cancer is still poorly understood. Preliminary work from our laboratory indicates that complement components are expressed locally in epithelial ovarian cancer. Furthermore, using a transplantation model of syngeneic murine ovarian carcinoma we have shown that tumor growth depends on C' activation, as genetic deletion of complement component 3 (C3) or pharmacologic inhibition of the C5a anaphylatoxin, a small cleavage fragments of C5 with potent inflammatory activities, hampered tumor growth. We hypothesize that massive C' activation occurs in tumors, which is harnessed by the tumors to establish themselves and grow through (i) activation of angiogenesis and (ii) direct effects on tumor cells, both of which may be in part be mediated by C' components and/or C'-activated cytokine networks. This proposal consists of three aims. The studies in Aim 1 are designed to define the role of complement in cancer establishment and progression. We will analyze the impact of complement inhibition on tumor establishment and progression through genetic approaches. We will use MISIIR-TAg, a transgenic mouse model of ovarian carcinoma with 100% phenotype penetrance, and test cancer phenotypes in MISIIR-TAg mice backcrossed onto backgrounds with various degrees of C' deficiency (C3"'", C5~'~, C3aR"'" or CSaR"'"). These studies will be complemented by pharmacologic inhibition of complement activation, or antagonism of complement anaphylatoxins. Aim 2 will examine the role of complement in tumor vascularization. We will examine autochtonous and transplantation tumors in C' sufficient mice, in mice deficient for C' components and in mice treated with C' antagonists, and quantify the effects of the C' deletion or antagonism on tumor vascularization. In addition, we will investigate the role of C', especially C3a and C5a anaphylatoxins, in tumor vascularization through the recruitment of hematopoietic stem cells, bone marrow endothelial progenitor cells and myeloid endothelial precursors. Aim 3 will examine the role of complement in the regulation of tumor cell death and proliferation. We will determine the ability of C3a anaphylatoxin to promote inflammatory activation, proliferation and survival in ovarian surface epithelium and ovarian cancer cells in vitro. This proposal addresses for the first time the involvement of C' as a modulator of the local inflammatory conditions that promote tumor establishment and/or progression. It will interact with Project 1 to understand how complement activation affects inflammatory networks and cell survival and proliferation differently in normal regeneration, immunopathologic repair and aberrant cancer growth. It will interact with Project 3 to test the effect of pharmacologic compounds targeting the complement cascade on cancer development and progression.