AGING AND OVARIAN CANCER

本申请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。将已经历体外转化事件的小鼠卵巢表面上皮细胞的稳定细胞系腹膜内注射到同基因C57 BL 6小鼠中。正如在卵巢癌患者中观察到的那样，多个肿瘤种植体在整个腹膜腔中发展。卵巢癌是一种衰老性疾病。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起作用的假设。当卵巢中的卵子供应耗尽时，就会出现更年期。卵泡停止发育，从而停止产生卵巢类固醇雌二醇和孕酮。然后激素反馈机制触发垂体促性腺激素分泌增加。因此，在女性绝经期，卵巢癌的发病率最高，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。除生殖衰老外，还发生与年龄相关的免疫衰老。因此，绝经前后卵巢癌的进展可能是生殖和免疫因素共同作用的结果。本提案中的实验将研究目前尚未解决的衰老和癌症领域。第一个目标是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，将在按时间顺序老化的小鼠中重新建立年轻的生殖激素表型。此外，通过去除卵巢，将在幼龄小鼠中诱导老化的生殖激素特征。将在每种情况下评估卵巢癌的进展。第二个目标是解决雌二醇的影响。孕酮和促性腺激素，单独和组合，在老年和年轻小鼠的癌症的进展。卵巢癌的进展将通过测量总体肿瘤负荷、肿瘤血管形成和VEGF表达、免疫参数（巨噬细胞、自然杀伤细胞、T细胞和IL-3产生）和参与转移的CSF-11 cfm 5/纤溶酶原激活物系统的表达来评估。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。

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.