Lysophospholipid in Neovascularization in Ovarian Cancer

描述（由申请人提供）：溶血磷脂酸（LPA）是一种天然存在的磷脂，可激活G蛋白偶联受体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由于观察到LPA在卵巢癌患者的腹水中以升高的水平存在。 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，仍然知之甚少。 我们最近进行了cDNA微阵列，以确定在卵巢癌细胞中LPA诱导和抑制基因的概况。 LPA诱导的最显著变化之一是显著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、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有助于卵巢癌的发病机制。 该假说将通过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）检查LPA在卵巢癌细胞中血管生成因子表达调节中的作用;和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与血管生成因子表达联系起来的细胞内信号网络。 然后我们将研究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因子。 LPA的潜在血管生成活性将通过体内血管生成试验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，并可能导致一种针对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蛋白偶联受体发出信号，这些受体是高度“药物化”的分子。 目前使用的所有药物中有一半以上都是针对这个细胞表面受体大家族的。

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.