Spontaneous malignant transformation of human ovarian surface epithelial cells in vitro.
OBJECTIVE
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.


METHODS
At various passages, cells were monitored for growth on collagen, response to tumor necrosis factor alpha and daunorubicin, immunohistochemistry and Western blot analysis of E-cadherin and beta-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-alpha and daunorubicin than earlier-passage cells. E-cadherin expression was limited to early-passage cells, whereas beta-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.
Gregoire
L
L
Department of Immunology and Microbiology, Karmanos Cancer Institute, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, MI 48201, USA.
Rabah
R
R
Schmelz
E M
EM
Munkarah
A
A
Roberts
P C
PC
Lancaster
W D
WD
D015820:Cadherins / Q000032:analysis; D018929:Cell Culture Techniques / Q000379:methods; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D003598:Cytoskeletal Proteins / Q000032:analysis; D004847:Epithelial Cells / Q000473:pathology*; D005260:Female; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D010053:Ovary / Q000473:pathology*; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D051176:beta Catenin; C059731:oncogene protein E7, Human papillomavirus type 16