Lysophospholipid in Neovascularization in Ovarian Cancer

描述(申请人提供)：溶血磷脂酸(LPA)，一种自然产生的磷脂，激活G蛋白偶联受体的内皮分化基因亚家族的不同成员，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可促进卵巢癌细胞的增殖、存活、耐药性和运动能力。然而，LPA在卵巢肿瘤发生中的确切作用，特别是在体内的作用，仍然知之甚少。我们最近进行了基因芯片的研究，以确定LPA诱导和抑制的卵巢癌细胞基因的表达谱。LPA诱导的最显著的变化之一是显著诱导促血管生成因子IL-6、IL-8、生长相关癌基因a(GroA)和血管内皮生长因子(VEGF)，提示血管生成因子是LPA在卵巢癌细胞中的主要靶基因。这些LPA诱导的因子是血管生成、肿瘤发生和肿瘤进展的重要介质。特别是，卵巢癌患者血清IL-6和IL-8水平高与化疗反应差和预后差相关。我们推测LPA刺激血管生成因子的表达和新生血管参与了卵巢癌的发病机制。这一假说将通过三个特定的目的来检验：A)阐明LPA诱导促血管生成因子产生的机制；B)检测LPA在卵巢癌细胞中调节血管生成因子表达的作用；以及C)确定LPA在新生血管中的作用。LPA受体和连接LPA与血管生成因子表达的细胞内信号网络将在卵巢癌细胞中被识别。然后，我们将研究LPA是否是卵巢癌细胞血管生成因子表达的主要内源性调节因子。LPA的潜在血管生成活性将通过体内血管生成实验和裸鼠移植瘤模型进行研究。这些研究将提高我们对卵巢癌发生的理解，并可能导致针对LPA受体和LPA产生的新疗法。作为一种小的磷脂分子，LPA通过G蛋白偶联受体传递信号，G蛋白偶联受体是高度“可药物”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。

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.