Mechanism of Cox-2 Inhibition in Ovarian Cancer Prevention

Fox Chase Cancer Center, Philadelphia PA

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Abstract

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.