GROWTH REGULATION & TRANSFORMATION OF OVARIAN EPITHELIUM

生长调节

• 批准号: 3460391
• 负责人: ANDREW BERCHUCK
• 金额: $ 10.56万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-02-01 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3460391
• 关键词: aging; autocrine; colony stimulating factor; connective tissue stroma; epidermal growth factor; epithelium; estrogen receptors; fibroblast growth factor; growth factor; hormone regulation /control mechanism; human genetic material tag; human tissue; immunocytochemistry; insulinlike growth factor; interferons; interleukin 1; monoclonal antibody; neoplastic transformation; oncogenes; ovary; ovary neoplasms; paracrine; platelet derived growth factor; progesterone receptors; receptor expression; tissue /cell culture; tumor necrosis factor alpha; tumor suppressor genes

Although most ovarian cancers arise from the surface epithelium, little is known regarding the biology of these cells. We have established human ovarian epithelial cells in culture to study their growth and transformation. In preliminary experiments, we have shown, 1) that epidermal growth factor stimulates proliferation of ovarian epithelial cells, and 2) that these cells both produce active transforming growth factor-beta (TGFbeta) and are growth inhibited by TGF-beta. In this proposal we will seek other peptide growth factors or steroid hormones that affect proliferation of ovarian epithelium and identify cells in the ovary that produce these factors. Relevant autocrine and paracrine growth regulatory pathways will be defined using monoclonal antibodies to neutralize the candidate growth factors or to block their receptors. Since ovulation is thought to be a stimulus to proliferation of ovarian epithelium and uninterrupted ovulation is associated with ovarian cancer, we will investigate whether the hormonal milieu after ovulation plays a role in stimulating growth of ovarian epithelium. We will test the hypothesis that estrogen or other hormones may decrease production of TGF-beta or response to this growth factor thereby down-regulating inhibition and stimulating growth. Since ovarian cancer is associated with aging, and we have shown that most ovarian cancer cell lines are relatively resistant to TGF-beta, we will examine the effect of aging on growth regulation of ovarian epithelial cells by TGF-beta. It is possible that loss of this growth inhibitory pathway with aging might play a role in the development of some ovarian cancers. We also have found that two growth regulatory genes, HER-2/neu and p53, are activated in a significant proportion of ovarian cancers. It is not known, however, whether activation of these oncogenes is an early event in ovarian carcinogenesis. To address this issue, we will evaluate expression of these-oncogenes in epithelial cells from normal ovaries and atypical ovarian epithelial cells from normal ovarian tissue in patients with early stage ovarian cancer and familial ovarian cancer. Since aging and uninterrupted ovulation have been associated with the development of ovarian cancer, we will investigate whether activation of HER-2/neu or p53 is seen more frequently in ovarian epithelial cells from older women and those with a history of uninterrupted ovulation. An increased understanding of growth regulation and transformation of human ovarian epithelium may lead to improvements in diagnosis, treatment and prevention of ovarian cancer.

尽管大多数卵巢癌起源于表面上皮，但很少有 关于这些细胞的生物学已知。 我们建立了人类 培养卵巢上皮细胞以研究其生长和 转变。 在初步实验中，我们已经证明，1） 表皮生长因子刺激卵巢上皮增殖 细胞，2) 这些细胞都产生活跃的转化生长 因子-β (TGFbeta) 并受 TGF-β 抑制生长。 在这个 建议我们将寻求其他肽生长因子或类固醇激素 影响卵巢上皮的增殖并识别卵巢中的细胞 产生这些因素。 相关的自分泌和旁分泌生长 将使用单克隆抗体来定义监管途径 中和候选生长因子或阻断其受体。 自从 排卵被认为是卵巢增殖的刺激因素 上皮细胞和不间断的排卵与卵巢癌有关， 我们将调查排卵后的荷尔蒙环境是否发挥作用 具有刺激卵巢上皮细胞生长的作用。 我们将测试 假设雌激素或其他激素可能会减少 TGF-β 或对该生长因子的反应从而下调 抑制和刺激生长。 由于卵巢癌与 衰老，我们已经证明大多数卵巢癌细胞系相对 对 TGF-β 具有抵抗力，我们将检查衰老对生长的影响 TGF-β对卵巢上皮细胞的调节。 有可能的是 随着衰老，这种生长抑制途径的丧失可能在 一些卵巢癌的发展。 我们还发现两个增长 调节基因 HER-2/neu 和 p53 在显着的情况下被激活 卵巢癌的比例。 然而，尚不清楚是否 这些癌基因的激活是卵巢癌发生的早期事件。 为了解决这个问题，我们将评估这些癌基因的表达 来自正常卵巢的上皮细胞和非典型卵巢上皮细胞 来自早期卵巢癌患者的正常卵巢组织 家族性卵巢癌。 由于衰老和不间断的排卵已成为 与卵巢癌的发展相关，我们将调查 HER-2/neu 或 p53 的激活是否在卵巢中更常见 来自老年女性和有不间断病史的女性的上皮细胞 排卵。 加深对生长调节和 人类卵巢上皮的转化可能会改善 卵巢癌的诊断、治疗和预防。