Mechanism of Cox-2 Inhibition in Ovarian Cancer Prevention

抑制 Cox-2 预防卵巢癌的机制

• 批准号: 6958678
• 负责人: XiangXi Mike Xu
• 金额: $ 8.88万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-22 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6958678
• 关键词: basement membrane; biological signal transduction; cancer prevention; chemoprevention; clinical research; collagenase; genetically modified animals; granulosa cell; histopathology; human subject; in situ hybridization; laboratory mouse; laminin; neoplasm /cancer epidemiology; neoplastic transformation; ovary neoplasms; prostaglandin endoperoxide synthase; prostaglandin inhibitors; proteolysis; tissue /cell culture; basement membrane; biological signal transduction; cancer prevention; chemoprevention; clinical research; collagenase; genetically modified animals; granulosa cell; histopathology; human subject; in situ hybridization; laboratory mouse; laminin; neoplasm /cancer epidemiology; neoplastic transformation; ovary neoplasms; prostaglandin endoperoxide synthase; prostaglandin inhibitors; proteolysis; tissue /cell culture

Epidemiological and experimental data support the use of non-steroidal anti-inflammatory drugs (NSAIDs), including specific inhibitors of Cox-2, as chemopreventive agents in a number of epithelial cancers. In general, it has been suggested that the inhibitors limit Cox-2-catalyzed production of prostaglandins, which may affect cell proliferation, apoptosis, anti-inflammatory responses, and angiogenesis. Based on our recent observations in ovarian cancers and from studies in animal models, we propose here a new mechanism for the chemopreventive activity of Cox-2 inhibitors in ovarian cancers, related to the integrity of the epithelial basement membrane. In the normal premenopausal ovary, the gonadotropins induce Cox-2 expression following the pre-ovulatory phase of follicular maturation. Cox-2 induction signals the initiation of the ovulatory phase, an inflammatory-like biological process. Moreover, prostaglandins, the products of Cox-2 activation, are believed to activate/induce collagenase and proteolysis and decrease the synthesis of the basement membrane components in both granulosa and ovarian surface epithelial cells. A recent study of pre-neoplastic lesions of human ovarian tumors suggests that the collagen IV- and laminin-containing basement membrane of the ovarian surface epithelium is lost prior to morphological transformation of the epithelial cells, suggesting that without an intact basement membrane, the surface epithelium represents a precursor lesion and subsequent genetic and epigenetic changes will lead to overt neoplastic transformation and tumorigenicity. By inhibiting Cox-2, the loss of basement membrane of the ovarian surface epithelium may be lessened and neoplastic transformation of the ovarian surface epithelial cells may be prevented. We propose to investigate the occurrence of basement membrane loss and Cox-2 overexpression in pre-neoplastic lesions of human ovaries from prophylactic oophorectomies of women from high-risk breast and ovarian cancer families. To investigate the mechanisms, we will also examine the effects and cellular signaling pathways of gonadotropin stimulation on the expression of Cox-2, collagen IV, laminin, and MMPs in ovarian surface epithelial cells in culture. The effect of Cox-2 overexpression will be assessed using ovarian surface epithelial-specific transgenic mice. We will also initiate a clinical trial to examine the effect of daily oral intake of Cox-2 inhibitors on the basement membrane integrity and occurrence of pre-neoplastic lesions in ovaries from prophylactic oophorectomies of women from high-risk breast and ovarian cancer families. The reduced loss of basement membrane and reduced number of pre-neoplastic lesions will be used as surrogate endpoints for the preventive activity of Cox-2 inhibitors in ovarian cancer. These studies will help to understand the etiology of ovarian cancer related to gonadotropin stimulation and provide a mechanism(s) for the chemopreventive activity of Cox-2 inhibitors. The ultimate goal will explore the use of Cox-2 inhibitors for chemoprevention of ovarian cancer.

流行病学和实验数据支持使用非甾体类抗炎药（NSAIDS），包括COX-2的特定抑制剂，作为许多上皮癌症中的化学预防剂。通常，已经提出抑制剂限制了前列腺素的COX-2催化产生，这可能会影响细胞增殖，凋亡，抗炎反应和血管生成。基于我们最近在卵巢癌中的观察结果以及在动物模型中的研究中，我们在这里提出了一种新的机制，用于与卵巢癌中Cox-2抑制剂化学预防活性，与上皮基底膜的完整性有关。在正常的绝经前卵巢中，促性腺激素在卵泡前成熟前卵巢阶段诱导COX-2表达。 COX-2诱导信号标志着排卵阶段的启动，这是一种炎症样生物学过程。此外，前列腺素是COX-2激活的产物，可以激活/诱导胶原酶和蛋白水解 并减少颗粒和卵巢表面上皮细胞中基底膜成分的合成。最近对人卵巢肿瘤的肿瘤前病变的研究表明，卵巢表面上皮的胶原蛋白静脉注射和含层粘连蛋白的基底膜在上皮细胞的形态转化之前就失去 病变以及随后的遗传和表观遗传变化将导致明显的肿瘤转化和肿瘤性。通过抑制COX-2，可以减少卵巢表面上皮的基底膜损失，并可以防止卵巢表面上皮细胞的肿瘤转化。我们建议研究基底膜损失和COX-2过表达的发生在高风险乳腺癌和卵巢癌的女性预防性卵巢卵巢的肿瘤前病变中 家庭。为了研究这些机制，我们还将检查促性腺激素刺激对培养中卵巢表面上皮细胞中COX-2，胶原蛋白IV，层粘连蛋白和MMPs表达的作用和细胞信号传导途径。 COX-2过表达的影响将使用卵巢表面上皮特异性转基因小鼠进行评估。我们还将启动一项临床试验，以检查COX-2抑制剂每天口服摄入对地下膜完整性的影响，以及来自高风险乳腺癌和卵巢癌家族的预防性卵巢卵巢卵巢中卵巢中肿瘤前病变的发生。基底膜的损失降低和减少肿瘤前病变的数量将用作COX-2抑制剂在卵巢癌中预防活性的替代端点。这些研究将有助于理解与促性腺激素刺激有关的卵巢癌的病因，并为COX-2抑制剂的化学预防活性提供了一种机制。最终目标将探索COX-2抑制剂用于化学预防卵巢癌的使用。