Mechanism of Cox-2 Inhibition in Ovarian Cancer Prevention

流行病学和实验数据支持使用非类固醇抗炎药(NSAIDs)，包括COX-2的特定抑制剂，作为一些上皮性癌症的化学预防药物。总的来说，有人认为这些抑制剂限制了COX-2催化的前列腺素的产生，这可能会影响细胞增殖、凋亡、抗炎反应和血管生成。根据我们最近在卵巢癌中的观察和动物模型的研究，我们在这里提出了COX-2抑制剂在卵巢癌中化学预防活性的新机制，与上皮基底膜的完整性有关。在正常绝经前卵巢中，促性腺激素在卵泡成熟的排卵前期诱导COX-2的表达。COX-2的诱导标志着排卵期的开始，这是一种类似炎症的生物过程。此外，环氧合酶-2激活的产物前列腺素被认为能够激活/诱导胶原酶和蛋白分解。 减少颗粒细胞和卵巢表面上皮细胞基底膜成分的合成。最近对人卵巢肿瘤癌前病变的一项研究表明，卵巢表面上皮的IV型胶原和含层粘连蛋白的基底膜在上皮细胞形态转化之前就已经丢失，这表明在没有完整的基底膜的情况下，表面上皮是一种前体 病变以及随后的遗传和表观遗传学改变将导致明显的肿瘤转化和致瘤性。通过抑制COX-2，可减轻卵巢表面上皮细胞基底膜的丢失，防止卵巢表面上皮细胞的恶性转化。我们建议调查高危乳腺癌和卵巢癌患者预防性卵巢切除术后卵巢癌前病变中基底膜丢失和COX-2过度表达的发生情况。 家人。为了探讨其机制，我们还将检测促性腺激素刺激对培养的卵巢表面上皮细胞COX-2、IV型胶原、层粘连蛋白和MMPs表达的影响及其细胞信号转导途径。COX-2过表达的影响将使用卵巢表面上皮细胞特异的转基因小鼠进行评估。我们还将启动一项临床试验，以检验每天口服COX-2抑制剂对来自高危乳腺癌和卵巢癌家族的预防性卵巢切除术患者的基底膜完整性和卵巢癌前病变发生的影响。基底膜丢失的减少和癌前病变的减少将被用作COX-2抑制剂预防卵巢癌活性的替代终点。这些研究将有助于了解卵巢癌与促性腺激素刺激相关的病因学，并为COX-2抑制剂的化学预防作用提供机制(S)。最终目标是探索COX-2抑制剂在卵巢癌化学预防中的应用。

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.