Role of Oxidants & Angiogenesis in Kaposi's Sarcoma

氧化剂的作用

• 批准号: 6580881
• 负责人: Susan R Mallery
• 金额: $ 26.26万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6580881
• 关键词: Kaposi's sarcoma; angiogenesis; angiogenesis factor; cell proliferation; clinical research; cytokine; drug screening /evaluation; enzyme linked immunosorbent assay; fibroblast growth factor; free radicals; high performance liquid chromatography; human tissue; hyperplasia; immunocytochemistry; inflammation; neoplasm /cancer chemotherapy; neoplasm /cancer remission /regression; neoplastic process; nitrogen; nonhuman therapy evaluation; oxidative stress; oxidizing agents; polymerase chain reaction; tissue /cell culture; vascular endothelial growth factors; western blottings

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.

描述（由申请人提供）：临床和实验证据表明卡波西肉瘤（KS）最初是一种血管增殖性增生，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 细胞既产生血管生成因子又对血管生成因子做出反应，因此 KS 细胞既是血管生成分子的效应器又是靶标。 KS 环境的特点是促炎细胞因子水平升高和持续炎症，这些条件导致活性氧和氮的大量产生。我们实验室最近的研究显示了患者 KS 活检病变细胞内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 KS 菌株在氧化剂攻击后无法上调细胞保护酶和相关辅因子。这些临床发现和我们的实验数据表明，KS 的出现是由于细胞无法预防氧化应激的有害致瘤后果。氧化应激通过支持细胞增殖促进肿瘤形成，同时使关键的抗氧化剂和 DNA 修复酶失活，并诱导促血管生成环境。根据我们的结果以及报告的临床和实验数据，我们提出了以下假设：血管生成因子 VEGF 和 bFGF 与氧化应激结合促进卡波西肉瘤的发生和进展。此外，充当抗氧化剂或血管抑制剂的药物会破坏 KS 致瘤表型的发展。该假设将使用体外（培养的 KS 和人内皮细胞）和体内（移植到裸鼠中的 KS 细胞）进行测试。目标 1 研究将描述氧化应激在 KS 致瘤表型的发生和进展中的作用。目标 2 研究将调查药物在体外抑制 KS 致瘤表型的能力。目标 3 研究将评估控释药物在体内抑制 KS 肿瘤生长的能力。拟议的研究使用分子方法来确定完整的血管生成细胞因子 VEGF 和 bFGF 以及反应性物质的表达汇聚以促进 KS 发生和进展的机制。阐明这些相互作用不仅将阐明 KS 致病机制，还将确定 KS 治疗干预的位点。