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: 6919241
• 负责人: XIANJUN FANG
• 金额: $ 23.16万
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919241
• 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）：一种天然存在的磷脂酸（LPA），激活了G蛋白偶联受体亚科的内皮分化基因的不同成员，以引起多个细胞反应。 LPA首先是通过观察到卵巢癌患者腹水升高的观察到的，这首先与卵巢癌有关。 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，尤其是体内，仍然知之甚少。 我们最近进行了cDNA微阵列，以确定卵巢癌细胞中LPA诱导和抑制基因的特征。 LPA诱导的最引人注目的变化之一是促血管生成因子的戏剧性诱导，包括白介素6（IL-6），白介素8（IL-8），与生长相关的癌基因A（GROA）（GROA）（GROA）和血管内皮内皮生长因子（VEGF），这表明血管生成因子是主要靶因子的主要靶基因。 这些LPA诱导的因素是血管生成，肿瘤性和癌症进展的重要介体。 尤其是，卵巢癌患者中IL-6和IL-8的高血清水平与对化学疗法和预后不良的反应不佳相关。 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理。 该假设将通过3个特定目的进行检查：a）阐明LPA诱导促血管生成因子产生的机制； b）检查LPA在卵巢癌细胞中血管生成因子表达调节中的作用； c）确定LPA在新血管中的作用。 在卵巢癌细胞中将鉴定出LPA受体和将LPA与血管生成因子表达联系起来的细胞内信号传导网络。 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性调节剂。 LPA的潜在血管生成活性将通过体内血管生成测定法和裸小鼠异种移植模型研究。 这些研究将提高我们对卵巢癌发生的理解，并有可能导致针对LPA受体和LPA产生的新型治疗。 作为一个小的磷脂分子，LPA通过G蛋白偶联受体信号，这些受体高度“可吸毒”。 当前使用中所有药物的一半以上针对这一大型细胞表面受体。