Lysophospholipid Mediators in Ovarian Cancer

描述（由申请人提供）：癌细胞增殖由 正常细胞通路的过度表达或突变激活， 控制细胞生长和分化。最近的研究表明， 受体介导的脂质生长因子溶血磷脂酸的作用 (LPA)在卵巢癌的病因学中起着核心作用。增长， 卵巢癌细胞的侵袭性和对化疗药物的抗性， 都依赖于LPA卵巢癌细胞合成LPA， 介导剂进入腹水，腹水在腹膜中积聚并沐浴 腹部肿瘤目前晚期卵巢癌的治疗方法包括 手术、放疗和化疗并没有提高 疾病因此，靶向LPA的合成和作用可能提供一种 卵巢癌药物干预的新治疗策略。 尽管参与对LPA反应的受体和信号通路是 令人惊讶的是，人们对酶和细胞的了解很少。 参与LPA合成、释放和失活的过程。我们有 鉴定了磷脂酶和脂质磷酸酶，它们在 LPA和相关生物活性脂质介质的合成和代谢。的 本提案中描述的研究目标是定义酶， 参与卵巢癌LPA合成和失活的途径 细胞这些途径的分子遗传学和药理学操作 将使我们能够评估针对LPA的治疗潜力， 卵巢癌的治疗方法成功完成 研究将提供框架和动力，以开发新的有效的 卵巢癌的治疗方法

DESCRIPTION (provided by applicant): Cancer cell proliferation is driven by overexpression or mutational activation of normal cellular pathways that control cell growth and differentiation. Recent work suggests that autocrine actions of the receptor-directed lipid growth factor lysophosphatidic adid (LPA) play a central role in the etiology of ovarian cancer. Growth, invasiveness and resistance to chemotherapeutics of ovarian cancer cells are all dependent on LPA. Ovarian cancer cells synthesize LPA and release this mediator into ascites fluid which accumulates in the peritoneum and bathes abdominal tumors. Current therapies for late stage ovarian cancer that include surgery, radiation and chemotherapy have not improved cure rates for the disease. Targeting the synthesis and actions of LPA may therefore provide a novel treatment strategy for pharmacological intervention in ovarian cancer. Although the receptors and signaling pathways involved in responses to LPA are well understood surprisingly little is known about the enzymes and cellular processes involved in LPA synthesis, release and inactivation. We have identified phospholipases and lipid phosphatases that play critical roles in the synthesis and metabolism of LPA and related bioactive lipid mediators. The goal of the research described in this proposal is to define the enzymes and pathways involved in the synthesis and inactivation of LPA by ovarian cancer cells. Molecular genetic and pharmacological manipulation of these pathways will allow us to evaluate the potential for therapies that target LPA metabolism in treatment of ovarian cancer. Successful completion of the research will provide the framework and impetus to develop novel effective therapeutics for ovarian cancer.