Role of Oxidants & Angiogenesis in Kaposi's Sarcoma

描述(申请人提供)：临床和实验证据表明，卡波西肉瘤(KS)最初是一种血管增生性增生，利用自分泌和旁分泌生长环促进进展为高度血管生成的肉瘤。由于KS细胞既能产生血管生成因子，又能对血管生成因子作出反应，因此KS细胞既是血管生成分子的效应者，又是血管生成分子的靶点。KS环境的特点是促炎细胞因子水平升高和持续的炎症，这些条件导致活性氧和氮物种的高产生。我们实验室最近的研究表明，患者KS活检组织中的皮损细胞中存在持续氧化应激的原位证据。我们实验室的其他研究表明，从这些KS活检中获得的培养的KS菌株在氧化剂攻击后未能上调细胞保护酶和相关的辅助因子。这些临床发现和我们的实验数据表明，KS是由于细胞无法预防氧化应激的有害和致癌后果而产生的。氧化应激通过支持细胞增殖促进肿瘤的形成，同时使关键的抗氧化剂和DNA修复酶失活，并诱导促进血管生成的环境。根据我们的研究结果以及已报道的临床和实验数据，我们提出了以下假设：血管生成因子血管内皮生长因子和碱性成纤维细胞生长因子与氧化应激共同促进了卡波西肉瘤的发生和发展。此外，作为抗氧化剂或血管抑制剂的药物将扰乱KS致瘤表型的发展。这一假设将在体外(培养的KS细胞和人类内皮细胞)和体内(KS细胞移植到裸鼠体内)两种情况下进行验证。目的1研究将确定氧化应激在KS致瘤表型的发生和发展中的作用。目的研究药物体外抑制KS细胞致瘤表型的能力。目的评价控释药物体内抑制KS肿瘤生长的能力。建议的研究使用分子方法来确定完整的血管生成细胞因子血管生成因子和碱性成纤维细胞生长因子的表达与活性物种融合以促进KS的发生和发展的机制。阐明这些相互作用不仅将阐明KS的发病机制，而且还将确定KS治疗干预的部位。

DESCRIPTION (provided by applicant): Clinical and experimental evidence imply that Kaposi's sarcoma (KS) is initially an angioproliferative hyperplasia that employs autocrine and paracrine growth loops to facilitate progression to a highly angiogenic sarcoma. Because KS cells both produce and respond to angiogenic factors, KS cells are both effectors and targets of angiogenic molecules. The KS milieu is characterized by elevated levels of proinflammatory cytokines and persistent inflammation, conditions which result in high production of reactive oxygen and nitrogen species. Recent studies from our laboratory have shown in situ evidence of ongoing oxidative stress within lesional cells of patients' KS biopsies. Other studies from our laboratory have shown that cultured KS strains obtained from these KS biopsies fail to upregulate cytoprotective enzymes and associated cofactors after oxidant challenge. These clinical findings and our experimental data indicate that KS arises due to a cellular inability to prevent the deleterious, tumorigenic consequences of oxidative stress. Oxidative stress promotes tumor formation by supporting cell proliferation, while it simultaneously inactivates key antioxidant and DNA repair enzymes, and induces a pro-angiogenic environment. Based on our results and reported clinical and experimental data, we have developed the following hypothesis: The angiogenic factors VEGF and bFGF in conjunction with oxidant stress facilitate the development and progression of Kaposi's sarcoma. Furthermore, agents that act as antioxidants or angiostatics will disrupt development of the KS tumorigenic phenotype. This hypothesis will be tested using both in vitro (cultured KS and human endothelial cells) and in vivo (KS cells transplanted in nude mice). Aim 1 studies will characterize the role of oxidative stress in development and progression of the KS tumorigenic phenotype. Aim 2 studies will investigate the ability of pharmacologic agents to suppress the KS tumorigenic phenotype in vitro. Aim 3 studies will evaluate the ability of controlled-release pharmacologic agents to inhibit growth of KS tumors in vivo. The proposed studies use a molecular approach to identify mechanisms by which expression of the complete angiogenic cytokines VEGF and bFGF and reactive species converge to facilitate KS development and progression. Elucidation of these interactions will not only clarify KS pathogenic mechanisms, but will also identify sites for KS therapeutic intervention.