| Abstract: | To investigate the cellular mechanisms of ovarian epithelial carcinogenesis, a series of progressively transformed rat ovarian surface epithelial (ROSE) cell lines were developed and studied. Transfection of a primary ROSE and an immortalized ROSE line (ROSE 199) with pSV3neo (SV40 T-antigen) yielded transformed lines which retained epithelial morphology, exhibited anchorage-independence and formed tumors in athymic mice. Histologically, one line formed tumors which resembled serous adenocarcinoma of the ovary. Transfection of ROSE 199 with pSV2neo/c-H-ras[^EJ] resulted in a malignant cell line which appeared fibroblast-like in culture, grew rapidly in soft agar and formed invasive sarcomas in both athymic mice and immunocompetent rats. Passage of the SV40-transformed lines through athymic mice yielded tumor-derived cell lines which exhibited a shift towards fibroblast-like morphology and enhanced anchorage-independence. In vitro transformation of both ROSE and ROSE 199 resulted in a loss of keratin expression, an epithelial-specific marker. Gap junctional intercellular communication (GJIC) and cell-cell adhesion were studied in this series of ROSE cell lines. SV4O-transformation of ROSE and ROSE 199 was not associated with any significant deviations in the rates of GJIC; however, c-H-rasEJ transformation of ROSE 199 resulted in a significant reduction in GJIC between adjoining cells. Tumorigenic selection was accompanied by a reduction in GJIC as the tumor-derived ROSE lines exhibited lower rates of GJIC compared to their parental lines. Tumorigenic selection of the SV40-transformed lines, in addition to ras[^EJ]-transformation of ROSE 199, also resulted in a transition of in vitro migration as continuous epithelial sheets to the dissociation of individual cells. This apparent shift in cell adhesiveness was associated with reduced expression of the E-cadherin cell adhesion molecule. These data suggest that neoplastic progression of the ovarian surface epithelium may be associated with a loss of the differentiation marker keratin, as well as a concomitant reduction in GJIC and cell-cell adhesive characteristics. This series of cell lines may prove useful in studies focusing on the mechanisms of metastatic progression during ovarian carcinogenesis. |
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