Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in Western countries. A better understanding of the etiology and risk factors associated with this disease is crucial for the development of early detection protocols as well as more effective therapies. Epidemiological data has shown that the risks of EOC are highest among peri- or post- menopause women, while increased parity or the use of oral contraceptives is preventive. These data suggest that alterations in reproductive factors are associated with ovarian cancer risks; however, the molecular mechanisms underlying such a link remain to be understood. For decades, EOC was believed to arise from the epithelium that surrounds the ovarian surface, yet this concept fails to explain the morphological resemblance of ovarian epithelial neoplasms with the epithelial cells of the Mullerian-derived female reproductive tract. Alternative ideas have argued that EOC may originate from extra- or para-ovarian tissues such as the fallopian tube and ovarii rete. Studies of the origin of EOC will provide a better understanding of the disease and advance the protocols for early diagnosis. The aims for this thesis are to establish in vivo ovarian tumor models based on the germ cell deficient Wv/Wv mice that mimicking menopausal physiology. The Wv mice harbor a point mutation in c-Kit, which reduces its tyrosine kinase activity to about 1%, resulting in a premature loss of ovarian germ cells and follicles that recapitulates the initiation of menopause in human. We have developed ovarian tumor models by deleting the tumor suppressor genes p53 or p27kip1 in Wv/Wv mice. We found that both Wv/Wv:p27+/- and Wv/Wv :p27 -/- mice developed ovarian epithelial tumors, which consist of papillary structures lined by hyperchromatic neoplastic cells. Positive Cytokeratin 8 (CK8) staining indicated the epithelial origin of these tumors. In vitro primary cultures of mouse ovarian surface epithelial (MOSE) cells from wildtype, p27+/- and p27 -/- mice further confirmed the growth advantage caused by p27 deficiency. However, neither p27 +/- nor p27 -/- MOSE cells were transformed in vitro, probably due to the compensatory increase of cyclin dependent kinase inhibitor (CKI) proteins including p21, p16, p19. When p53 was deleted unilaterally in the ovarian surface epithelial cells of Wv/Wv:p53 loxP/loxP mice by single administration of Adenovirus containing Cre activity (Ad-Cre), ovarian tumors developed after long latency. The ovarian tumors were significantly enlarged when compared with the uninfected ovary from the same mouse. However, most of the lesions in Wv:p53 conditional knockout tumors was negative for epithelial and follicular markers. In vitro deletion of p53 in MOSE cells significantly increased the proliferation and passage numbers of these cells. A compensatory increase of the CKI protein p16, as well as the cellular senescence level was also observed in p53 deleted MOSE cells, suggesting that p53 deletion alone was not sufficient to bypass p16- mediated tumor defense mechanisms in MOSE cells. Taken together, single deletion of p27 and p53 significantly amplified the phenotype of benign tubular adenomas in Wv/Wv mouse. However, neither p27 nor p53 deletion was sufficient to induce the development of malignant ovarian carcinomas in Wv/Wv mice, probably due to the up-regulation of CKI family proteins such as p21, p16 or p19.
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