Lysophospholipid in Neovascularization in Ovarian Cancer

溶血磷脂在卵巢癌新血管形成中的作用

• 批准号: 6774357
• 负责人: XIANJUN FANG
• 金额: $ 23.18万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6774357
• 关键词: angiogenesis; angiogenesis factor; ascites; athymic mouse; biological signal transduction; carcinogenesis; cell line; cell surface receptors; chemical structure function; clinical research; female; gene expression; human tissue; interleukin 6; interleukin 8; lysophospholipids; molecular oncology; neoplasm /cancer blood supply; neoplastic cell; ovary neoplasms; small molecule; vascular endothelial growth factors; xenotransplantation

DESCRIPTION (provided by applicant): Lysophosphatidic acid (LPA), a naturally occurring phospholipid, activates distinct members of the endothelial differentiation gene subfamily of G protein-coupled receptors to elicit multiple cellular responses. LPA was first implicated in ovarian cancer by the observation that LPA is present at elevated levels in ascites of ovarian cancer patients. LPA stimulates proliferation, survival, drug resistance and motility of ovarian cancer cells. However, the exact role of LPA in ovarian oncogenesis, particularly in vivo, remains poorly understood. We have recently performed cDNA microarrays to determine the profile of LPA-induced and repressed genes in ovarian cancer cells. One of the most striking changes induced by LPA was the dramatic induction of pro-angiogenic factors including interleukin 6 (IL-6), interleukin 8 (IL-8), growth-related oncogene a (GROa) and vascular endothelial growth factor (VEGF), suggesting that angiogenic factors are major target genes of LPA in ovarian cancer cells. These LPA-induced factors are important mediators of angiogenesis, tumorigenicity and cancer progression. In particular, high serum levels of IL-6 and IL-8 in ovarian cancer patients correlate with poor response to chemotherapy and poor prognosis. We hypothesize that LPA stimulation of angiogenic factor expression and neovascularization contributes to the pathogenesis of ovarian cancer. The hypothesis will be examined through 3 specific aims: A) To elucidate the mechanism by which LPA induces production of pro-angiogenic factors; B) To examine the role of LPA in the regulation of angiogenic factor expression in ovarian cancer cells; and C) To determine the role of LPA in neovascularization. LPA receptors and the intracellular signaling networks that link LPA to expression of angiogenic factors will be identified in ovarian cancer cells. We will then examine whether LPA is a primary endogenous regulator of angiogenic factor expression in ovarian cancer cells. The potential angiogenic activity of LPA will be studied by in vivo angiogenesis assay and in nude mouse xenograft models. These studies will improve our understanding of ovarian carcinogenesis and will potentially lead to a novel therapy targeting LPA receptors and LPA production. As a small phospholipid molecule, LPA signals through G protein-coupled receptors that are highly "drugable" molecules. More than half of all drugs in current use target this large family of cell surface receptors.

描述（由申请人提供）：溶血磷脂酸（LPA）是一种天然存在的磷脂，激活G蛋白偶联受体的内皮分化基因亚家族的不同成员以引发多种细胞反应。 LPA 首次与卵巢癌有关，是因为观察到卵巢癌患者腹水中 LPA 水平升高。 LPA 刺激卵巢癌细胞的增殖、存活、耐药性和运动性。 然而，LPA 在卵巢肿瘤发生中的确切作用，特别是在体内，仍知之甚少。 我们最近进行了 cDNA 微阵列以确定卵巢癌细胞中 LPA 诱导和抑制基因的概况。 LPA 引起的最显着的变化之一是显着诱导促血管生成因子，包括白细胞介素 6 (IL-6)、白细胞介素 8 (IL-8)、生长相关癌基因 a (GROa) 和血管内皮生长因子 (VEGF) ），表明血管生成因子是卵巢癌细胞中LPA的主要靶基因。 这些 LPA 诱导因子是血管生成、致瘤性和癌症进展的重要介质。 特别是，卵巢癌患者血清中高水平的 IL-6 和 IL-8 与化疗反应不佳和预后不良相关。 我们假设 LPA 刺激血管生成因子表达和新血管形成有助于卵巢癌的发病机制。 该假设将通过 3 个具体目标进行检验：A) 阐明 LPA 诱导促血管生成因子产生的机制； B) 考察LPA对卵巢癌细胞血管生成因子表达的调节作用； C) 确定 LPA 在新生血管形成中的作用。 将在卵巢癌细胞中鉴定 LPA 受体和将 LPA 与血管生成因子的表达联系起来的细胞内信号网络。 然后我们将检查 LPA 是否是卵巢癌细胞中血管生成因子表达的主要内源调节因子。 LPA 的潜在血管生成活性将通过体内血管生成测定和裸鼠异种移植模型进行研究。 这些研究将提高我们对卵巢癌发生的理解，并有可能开发出一种针对 LPA 受体和 LPA 产生的新疗法。 作为一种小磷脂分子，LPA 通过 G 蛋白偶联受体发出信号，这些受体是高度“可成药”的分子。 目前使用的所有药物中有一半以上针对这一大家族的细胞表面受体。