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: 7241458
• 负责人: XIANJUN FANG
• 金额: $ 21.92万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7241458
• 关键词: Angiogenic Factor; Animals; Ascites; Biological Assay; Cancer Patient; Cancer cell line; Cell Surface Receptors; Complementary DNA; Development; Disease; Drug resistance; Employee Strikes; Family; G-Protein-Coupled Receptors; Gene Targeting; Genes; Growth; Growth Factor; IL8 gene; Interleukin-6; Interleukin-6 Overexpression; Interleukin-8; Lead; Link; Lipids; Lysophosphatidic Acid Receptors; Lysophospholipids; Malignant neoplasm of ovary; Mediating; Mediator of activation protein; Modeling; Molecular; Nude Mice; Numbers; Oncogenes; Outcome; Ovarian; Pathogenesis; Peritoneal Fluid; Pharmaceutical Preparations; Pharmacologic Substance; Phospholipids; Production; Protein Overexpression; Regulation; Role; Serum; Signal Transduction; Tumor Angiogenesis; Tumorigenicity; VEGFA gene; Vascular Endothelial Growth Factors; Xenograft Model; angiogenesis; cDNA Arrays; cancer cell; carcinogenesis; cell motility; chemotherapy; cytokine; improved; in vivo; lysophosphatidic acid; matrigel; member; neovascularization; novel; outcome forecast; receptor; response; tumor progression; tumorigenesis

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，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首先与卵巢癌有关，因为观察到LPA在卵巢癌患者的腹水中水平升高。LPA刺激卵巢癌细胞增殖、存活、耐药和运动。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微阵列来确定lpa诱导和抑制卵巢癌细胞基因的谱。LPA诱导的最显著的变化之一是显著诱导促血管生成因子，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），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、致瘤性和癌症进展的重要介质。特别是，卵巢癌患者血清中IL-6和IL-8的高水平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的形成与卵巢癌的发病有关。这一假设将通过三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)探讨LPA在调控卵巢癌细胞血管生成因子表达中的作用；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受体和连接LPA与血管生成因子表达的细胞内信号网络。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实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，这是一种高度“可用药”的分子。目前使用的所有药物中有一半以上是针对这种细胞表面受体大家族的。