Complement in cancer establishment and growth

这项研究的长期目标是确定炎症的关键成分S通过其机制， 补体(C_1)系统影响肿瘤的建立和发展。两国之间的关系 炎症、先天免疫和癌症正变得越来越明显。尽管两者之间存在明显的联系 炎症和C‘系统，C’在癌症中的作用仍然知之甚少。前期工作来自 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的移植模型，我们已经证明了肿瘤 生长依赖于C‘的激活，如补体成分3(C3)的遗传缺失或药物抑制 在C5a过敏毒素中，C5的一小段裂解片段具有强大的炎症活性，阻碍了肿瘤 成长。我们假设在肿瘤中发生了大量的C‘活化，这被肿瘤利用来 通过(I)激活血管生成和(Ii)对肿瘤细胞的直接作用而建立和生长，两者都是 这可能部分是由C‘组分和/或C’激活的细胞因子网络介导的。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和 通过遗传方法取得进展。我们将使用MISIIR-TAG，一种卵巢转基因小鼠模型 具有100%表型外显率的癌症，并测试MISIIR标记小鼠的癌症表型。 背景不同程度的C‘缺乏(C3“’、C5~‘~、C3aR”’或CSAR“‘)。这些研究将是 辅以对补体激活的药物抑制或补体的拮抗 过敏毒素。目的2研究补体在肿瘤血管形成中的作用。我们将研究 C‘充足小鼠、C’成分缺乏小鼠和小鼠体内的自体和移植肿瘤 用C‘拮抗剂处理，并量化C’缺失或拮抗对肿瘤血管形成的影响。在……里面 此外，我们将研究C‘，特别是C3a和C5a过敏性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样细胞 内皮前体。目标3将研究补体在调节肿瘤细胞死亡和 扩散。我们将测定C3a过敏性毒素促进炎症激活、增殖的能力 在体外培养的卵巢表面上皮细胞和卵巢癌细胞中存活。这项提案针对的是第一个 C‘作为促进肿瘤形成的局部炎症条件的调节器的时间 和/或进展。它将与项目1互动，了解补体激活如何影响炎症 网络与细胞存活和增殖在正常再生、免疫病理修复和 癌症的异常生长。它将与项目3互动，以测试药物化合物针对 补体级联作用于癌症的发生和发展。

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.