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Spontaneous Malignant Transformation of Human Ovarian Surface Epithelial Cells in Vitro¹

Department of Immunology and Microbiology [L. G., P. C. R.], Karmanos Cancer Institute [ L. G., E-M. S., A. M., W. D. L.], Departments of Pathology [R. R.] and Obstetrics and Gynecology [A. M., W. D. L.], and the Center for Molecular Medicine and Genetics [A. M., W. D. L.], Wayne State University School of Medicine, Detroit, Michigan 48201

Purpose: Epithelial ovarian cancer has no reliable marker for early detection and no known specific premalignant changes. Human ovarian surface epithelial (HOSE) cells expressing human papillomavirus type 16 (HPV-16) E6/E7 genes undergo crisis, and surviving cells exhibit an immortalized phenotype. Cells show an increasingly invasive phenotype on collagen rafts over time. To ascertain the nature of this aberrant growth, we characterized this spontaneous progression of HOSE cells from a benign to an invasive phenotype using histopathology, immunophenotyping, and tumorigenesis assays.

Experimental Design: At various passages, cells were monitored for growth on collagen, response to tumor necrosis factor and daunorubicin, immunohistochemistry and Western blot analysis of E-cadherin and ß-catenin, growth in soft agar, and tumor formation in immunodeficient mice.

Results: As passage number increased, cells became increasingly aggressive on collagen, with more pronounced focal stratification and invasion. Furthermore, late-passage cells were more resistant to the apoptotic effects of TNF- and daunorubicin than earlier-passage cells. E-cadherin expression was limited to early-passage cells, whereas ß-catenin was expressed regardless of passage. Cells invading collagen formed colonies in soft agar at low efficiency but were not tumorigenic in immunodeficient mice. Some cultures recovered from colonies grew in soft agar at high efficiencies, and one was tumorigenic.

Conclusions: HOSE cells expressing E6/E7, over time, develop characteristics of malignant cells and produce tumors consistent with an ovarian surface epithelium lineage. Progression of HOSE cells from a benign to an invasive phenotype in vitro may provide a model to dissect the progression of ovarian cancer.

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