Gonadotropins & Cox-2 in Ovarian Cancer Prevention

促性腺激素

• 批准号: 8082725
• 负责人: XiangXi Mike Xu
• 金额: $ 37.58万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8082725
• 关键词: Accounting; Address; Age; Aging; Apoptosis; Aspirin; Basement membrane; Benign; Biological; Biology; Cancer Etiology; Cancer Model; Chemicals; Contraceptive Agents; Development; Devices; Dose; Enzymes; Epidemiology; Epithelial Cells; Etiology; Funding; Gene Dosage; Genetic; Genotype; Germ Cells; Goals; Gonadotropins; Growth; Hormones; Implant; Incidence; Infusion procedures; Investigation; Knock-out; Knowledge; Lead; Longevity; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Menopause; Modeling; Morphology; Mus; Mutant Strains Mice; Mutation; Oncogenic; Oral Contraceptives; Organ Culture Techniques; Ovarian; Ovarian Follicle; Ovary; Pathway interactions; Peptide Hydrolases; Phenotype; Physiology; Point Mutation; Post-Menopausal Hormone Replacement Therapy; Postmenopause; Prevention strategy; Preventive; Progesterone; Progestins; Protein Tyrosine Kinase; Proto-Oncogene Protein c-kit; Reagent; Reproductive History; Risk; Risk Factors; Role; Study models; Surface; System; Testing; Translating; Tubular Adenoma; Tumor Biology; Variant; White Spots; adenoma; base; cancer risk; design; follow-up; inhibitor/antagonist; mouse model; mutant mouse model; neoplastic; null mutation; ovarian cancer prevention; ovarian neoplasm; practical application; premature; prevent; public health relevance; reproductive; research study; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Epidemiological observations have established ovarian cancer risk factors, such as high cancer incidence in peri- postmenopausal ages and preventive activity of oral contraceptives. However, the mechanisms for these well-established ideas remain obscure, and experimental systems are highly desirable to gain biological and mechanistic understanding of the epidemiological findings. Menopausal ovaries undergo morphological changes, known as "ovarian aging" which are implicated in the high incidence of ovarian cancer occurring during the peri-menopausal and immediate post-menopausal periods. We explore a germ cell-deficient Wv (white spotting variant) mutant mouse line to model the impact of menopausal physiology on the increased risk of ovarian cancer, and the model may also allow us to test preventive agents. The Wv mice harbor a point mutation in c-Kit that reduces the tyrosine kinase activity to about 1-5% (not a null mutation). The mutation results in a premature loss of ovarian germ cells and follicles, but other biological phenotypes are very mild and the mice have a near normal life span. The germ cell- deficient Wv mice recapitulate some of these post-menopausal alterations in ovarian morphology and develop tubular adenomas. Furthermore, addition of oncogenic mutation such as loss of p27kip1 or loss of p53 converts the ovarian adenomas into neoplastic tumors. In preliminary experiments, suppression of Cox-1 was found to delay ovarian follicle depletion in addition to suppressing tumor development. Among several proteolytic enzymes investigated, we found that uPA was elevated in Wv ovaries, and we speculate that uPA may be the underlying cause of Wv ovarian tumor phenotype. The goal of the proposal is to use the Wv mouse models with additional oncogenic mutation to study the mechanisms responsible for the menopausal increase in ovarian cancer risk and to test several potential preventive approaches. First, we will further study the roles of Cox-1 in ovarian germ cell and follicle maturation and survival, and ovarian tumor development (Aim 1). We also will investigate the importance of uPA in ovarian tumor formation using the Wv mouse models, and the ability of uPA inhibitors to reduce ovarian tumorigenesis (Aim 2). Lastly, we will use progestin to suppress gonadotropins in Wv mice to verify the "follicle depletion hypothesis". The experiments will reveal whether follicle depletion or increased gonadotropins is the principal cause of ovarian tumorigenesis in Wv mice (Aim 3). These studies will address a fundamental mechanism of ovarian cancer etiology related to reproductive factors and the roles and mechanisms of Cox-1, Cox-2, uPA, and progestins (oral contraceptives), which are potential preventive targets/agents for ovarian cancer. Successful completion of the experiments will further our understanding of the underlying mechanism for reproductive factors on ovarian cancer risk and provide rationale for possible preventive approaches for ovarian cancer. PUBLIC HEALTH RELEVANCE: In this application, we propose to study reproductive factors in ovarian tumor development. Further studies are to focus on Cox-1 and uPA, potential targets for preventive approaches and the use of aspirin, progestins, and WX-UK1 (a uPA inhibitor). These studies will verify the importance of follicle depletion in the development of ovarian neoplasms and provide new understanding of the etiology and tumor biology of ovarian cancer. The results may generate new understanding for the potential to prevent ovarian cancer and the mechanisms of progesterone/progestins in contraceptives and in postmenopausal hormone replacement therapy. Also, the studies will test if Cox and uPA pathways may be useful as targets for prevention of ovarian cancer targets, and provide an understanding of their mechanisms.

描述（由申请人提供）：流行病学观察已确定卵巢癌的危险因素，例如绝经后年龄的高癌症发病率和口服避孕药的预防活性。然而，这些既定想法的机制仍然模糊，非常需要实验系统来获得对流行病学发现的生物学和机制理解。 更年期卵巢会发生形态变化，称为“卵巢老化”，这与围绝经期和绝经后时期发生的卵巢癌高发有关。我们探索了生殖细胞缺陷的 Wv（白斑变体）突变小鼠系，以模拟更年期生理学对卵巢癌风险增加的影响，并且该模型还可以让我们测试预防药物。 Wv 小鼠的 c-Kit 存在点突变，可将酪氨酸激酶活性降低至约 1-5%（不是无效突变）。该突变导致卵巢生殖细胞和卵泡过早丧失，但其他生物表型非常轻微，小鼠的寿命接近正常。生殖细胞缺陷的 Wv 小鼠再现了绝经后卵巢形态的一些变化并发展为管状腺瘤。此外，添加致癌突变（例如 p27kip1 缺失或 p53 缺失）会将卵巢腺瘤转化为肿瘤。在初步实验中，发现抑制 Cox-1 除了抑制肿瘤发展之外，还可以延迟卵泡耗竭。在研究的几种蛋白水解酶中，我们发现uPA在Wv卵巢中升高，我们推测uPA可能是Wv卵巢肿瘤表型的根本原因。 该提案的目标是使用具有额外致癌突变的 Wv 小鼠模型来研究绝经期卵巢癌风险增加的机制，并测试几种潜在的预防方法。首先，我们将进一步研究Cox-1在卵巢生殖细胞和卵泡成熟和存活以及卵巢肿瘤发展中的作用（目标1）。我们还将使用 Wv 小鼠模型研究 uPA 在卵巢肿瘤形成中的重要性，以及 uPA 抑制剂减少卵巢肿瘤发生的能力（目标 2）。最后，我们将使用孕激素抑制Wv小鼠的促性腺激素，以验证“卵泡耗竭假说”。实验将揭示卵泡耗竭或促性腺激素增加是否是 Wv 小鼠卵巢肿瘤发生的主要原因（目标 3）。 这些研究将探讨与生殖因素相关的卵巢癌病因学的基本机制，以及 Cox-1、Cox-2、uPA 和孕激素（口服避孕药）的作用和机制，这些是卵巢癌的潜在预防靶标/药物。实验的成功完成将进一步了解生殖因素对卵巢癌风险的潜在机制，并为卵巢癌的可能预防方法提供理论依据。 公共健康相关性：在本申请中，我们建议研究卵巢肿瘤发展中的生殖因素。进一步的研究重点是 Cox-1 和 uPA，它们是预防方法的潜在靶标以及阿司匹林、孕激素和 WX-UK1（一种 uPA 抑制剂）的使用。这些研究将验证卵泡耗竭在卵巢肿瘤发生中的重要性，并为卵巢癌的病因学和肿瘤生物学提供新的认识。这些结果可能会对预防卵巢癌的潜力以及孕酮/孕激素在避孕药具和绝经后激素替代疗法中的机制产生新的认识。此外，这些研究还将测试 Cox 和 uPA 通路是否可用作预防卵巢癌的靶点，并提供对其机制的了解。