Ovarian cancer, the most frequently fatal gynecological malignancy, arises from the cells which cover the ovarian surface. We have developed a system to isolate and grow in vitro ovarian surface epithelial cells of the rat. These mesodermally derived epithelial cells undergo passage dependent spontaneous transformation in vitro. They lose the contact inhibited phenotype, gain the capacity for substrate independent growth, and form serous tumors histologically consistent with human ovarian cancer when injected into nude athymic mice. Detailed karyotypic analysis of two clonal cell lines and one mixed population of rat ovarian surface epithelial cells revealed in late passage changes consistent with tumor suppressor gene loss and oncogene activation. These changes consistently involved chromosomes 1 and 5. We have begun to characterize the chromosome 5 changes at the molecular level and show that the interferon loci map distal (at 5q 32) to the 5q22q23 region originally reported. Data generated in this preliminary study also gave the first experimental proof of the postulate that loss of a """"""""wild type"""""""" chromosome by mitotic nondisfunction and duplication of the remaining aberrent allele is one mechanism by which recessive somatic and germ line mutations can be fully unmasked. Information gained in this rat model will aid in the development of a similar model of the human ovarian surface epithelium. Together these models will allow us to determine the genetic bases for initiation of human ovarian cancer. To meet this ultimate goal we propose: 1 . Develop multiple cell lines from rat ovarian surface epithelial cells. After multiple in vitro passages, examine the cells in detail for the spontaneous appearance of features consistent with the transformed phenotype, and by stringent karyotypic analysis determine consistent cytogenetic changes related to the phenotype. 2. Based on leads from our cytogenetic analysis, determine the molecular genetic changes involved in the spontaneous development of the transformed and tumorigenic phenotype in rat ovarian surface epithelial cells. 3. Develop cell cultures of human ovarian surface epithelial cells derived from the ovaries of women without evidence of ovarian disease and women with a hereditary predisposition for ovarian cancer. After multiple in vitro passages, examine the cells for the appearance of features consistent with malignant transformation and determine the cytogenetic changes and molecular bases for the altered phenotype.
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