AGING AND OVARIAN CANCER

衰老与卵巢癌

• 批准号: 6050792
• 负责人: KATHERINE F ROBY
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-15 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6050792
• 关键词: T lymphocyte; age difference; animal old age; cytokine; disease /disorder model; estradiol; female; gonadotropins; hormone related neoplasm /cancer; laboratory mouse; macrophage; natural killer cells; neoplastic process; ovary neoplasms; progesterone; vascular endothelial growth factors

The objective of this application is to determine the effect of aging on the progression of ovarian cancer. A novel mouse model of ovarian cancer will be used. A stable cell line of mouse ovarian surface epithelial cells that has undergone an in vitro transformation event will be injected intraperitoneally into syngeneic C57BL6 mice. Multiple tumor implants develop throughout the peritoneal cavity, just as observed in women with ovarian cancer. Ovarian cancer is a disease of aging. The peak incidence of ovarian cancer is coincident with menopause and this epidemiological data has lead to the hypothesis that senescence of the female reproductive tract plays a role in the progression of ovarian cancer. Menopause results when the supply of ova in the ovaries is exhausted. Follicle development, and thus production of the ovarian steroids estradiol and progesterone, stops. Hormonal feedback mechanisms then trigger elevated secretion of pituitary gonadotropins. Thus, at the time of menopause in women, when the incidence of ovarian cancer is greatest, multiple hormonal changes occur, including decreased ovarian steroids and increased pituitary gonadotropins. In addition to reproductive senescence, age associated immunsenescence also occurs. Thus, the progression of ovarian cancer around the time of menopause likely may result from both reproductive and immune factors. The experiments in this proposal will investigate an area of aging and cancer not currently addressed. The First aim will determine progression of ovarian cancer in aged and young mice. In addition, a youthful reproductive hormonal phenotype will be re- established in chronologically aged mice by transplantation of young ovaries. Also, an aged reproductive hormonal profile will be induced in young mice by removing the ovaries. The progression of ovarian cancer will be assessed in each condition. The second aim will address the effects of estradiol. progesterone, and gonadotropins, alone and in combination, in aged and young mice on the progression of the cancer. Progression of ovarian cancer will be assessed by measuring overall tumor load, tumor vascularization and VEGF expression, immune parameters (macrophages, Natural Killer cells, T-cells, and IL-3 production), and expression of the CSF-llcfm5/plasminogen activator system involved in metastasis. These studies will utilize a novel model for the study of ovarian cancer. In addition, novel information will be obtained on the effects of aging, the aging reproductive system, and the aging immune system on the progression of ovarian cancer.

这项应用的目的是确定衰老对卵巢癌进展的影响。将使用一种新的卵巢癌小鼠模型。经过体外转化的稳定的小鼠卵巢表面上皮细胞系将被注射到同基因C57BL6小鼠的腹膜内。正如在卵巢癌妇女身上观察到的那样，在整个腹膜腔内都会出现多个肿瘤植入物。卵巢癌是一种老年性疾病。卵巢癌的发病高峰与绝经期一致，这一流行病学数据导致了女性生殖道衰老在卵巢癌进展中的作用的假说。当卵巢中的卵子供应耗尽时，就会导致更年期。卵泡发育停止，从而停止产生卵巢类固醇雌二醇和孕酮。荷尔蒙反馈机制随后会触发脑下垂体促性腺激素的分泌增加。因此，在女性绝经时，卵巢癌的发病率最高，会发生多种激素变化，包括卵巢类固醇减少和垂体促性腺激素增加。除了生殖衰老，年龄相关的免疫衰老也会发生。因此，卵巢癌在绝经前后的进展可能是生殖和免疫因素共同作用的结果。这项提案中的实验将调查一个目前尚未解决的老龄化和癌症领域。第一个目标将确定老年和年轻小鼠卵巢癌的进展。此外，通过移植年轻的卵巢，年轻的生殖激素表型将在按时间顺序老化的小鼠中重新建立。此外，通过摘除卵巢，将在幼鼠身上诱导衰老的生殖荷尔蒙特征。卵巢癌的进展将在每种情况下进行评估。第二个目标将解决雌二醇的影响。黄体酮和促性腺激素，单独和联合，在老年和年轻小鼠的癌症进展中。卵巢癌的进展将通过测量总的肿瘤负荷、肿瘤血管生成和血管内皮生长因子的表达、免疫参数(巨噬细胞、自然杀伤细胞、T细胞和IL-3产生)以及参与转移的脑脊液-11cfm5/纤溶酶原激活系统的表达来评估。这些研究将利用一种新的模型来研究卵巢癌。此外，还将获得关于衰老、衰老的生殖系统和衰老的免疫系统对卵巢癌进展的影响的新信息。