Abstract

Epithelial ovarian cancers account for approximately 85–90% of all ovarian cancer cases and are the most lethal among gynecological malignancies. Although epithelial ovarian cancer is curable if detected before its metastasis to pelvic and peritoneal secondary sites, a lack of readily discernable symptoms and reliable markers of early-stage disease result in most cases presenting at advanced stages, where the 5-yr survival rate is only 25–30%. Moreover, despite initial response of most advanced epithelial ovarian cancers to taxane and platinum-based chemotherapy, recurrence of drug-resistant cancers continues to be a concern. Although it is clear that more effective treatments for advanced disease and development of noninvasive screening approaches are required to improve the outcome for women who develop epithelial ovarian cancer, a major problem confronting the field has been defining key events in the etiology of this disease. Indeed, even defining the cell of origin has been controversial. Epithelial ovarian cancers are subdivided into various histological subtypes based upon their resemblance to the epithelia of Mullerian-derived reproductive tract structures. For example, serous cancer morphologically resembles Fallopian tube epithelium, mucinous cancers resemble cervical epithelium, and clear-cell and endometrioid cancers resemble uterine endometrium. These subtypes differ in incidence, prognosis, associated risk factors, sensitivity to chemotherapy, and gene mutations associated with predisposition or early events in malignant transformation. Whereas recent studies provide compelling evidence that high-grade serous ovarian cancer originates from cells within the distal Fallopian tube rather than the ovary (summarized in Ref. 1), other ovarian cancer histotypes are thought to arise from ovarian surface epithelial (OSE) cells lining the surface of the ovary. The OSE is not a true epithelium but rather is derived from the mesoderm and possesses both epithelial and mesenchymal characteristics. Similar to epithelial cells, the OSE synthesizes laminin and collagen IV, but also expresses vimentin and in culture secretes stromal matrix collagens (I and III) typical of mesenchymal cells (2). A normal function for this simple mesothelium has not been firmly established, but studies indicate it participates in events contributing to ovulation (2, 3). The mechanisms causing malignant transformation of OSE cells are unknown. A favored hypothesis is that many epithelial ovarian carcinomas arise from cortical epithelial inclusion cysts formed by the invagination of the OSE into underlying cortical stroma as a consequence of wound repair after ovulation or reduction of ovarian surface area which accompanies aging. These inclusions are thought to be normally short lived, with the cells undergoing apoptosis or conversion to stromal fibroblasts (4). However, failure to undergo either of these processes results in their exposure to mitogenic factors stimulated by wound repair after ovulation and to autocrine as well as paracrine and endocrine factors secreted by the surrounding ovarian stroma, which undergoes changes related to pregnancy and aging. Prolonged exposure has been hypothesized to render these cells more susceptible to neoplastic transformation. In vivo, OSE cells exhibit varying morphology including squamous, cuboidal, columnar, and pseudostratified columnar, likely reflecting signaling by the underlying pa-

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