Oncogenic transformation of human ovarian surface epithelial cells with defined cellular oncogenes.
Ovarian surface epithelium (OSE) is considered to give rise to epithelial ovarian carcinomas (EOCs). To elucidate early processes contributing to the development of EOCs from the OSE, two batches of primary human OSE cells were transduced with non-viral human genes (mutant Cdk4, cyclinD1 and hTERT) so as to efficiently establish normal diploid OSE cells without chromosomal instability. Then defined genetic alterations frequently observed in EOCs were transduced into the OSE cells. A combination of p53 inactivation and oncogenic Kras transduction did not confer tumor-forming ability in immunodeficient mice, though additional transduction of Akt or combined transduction of c-myc with bcl-2 did result in tumor formation. In the latter case, tumors demonstrated phenotypes reminiscent of human EOCs, including cytokeratin expression, a highly aggressive phenotype, metastatic behavior and formation of ascites. These results indicate that inactivation of p53 and activation of the Ras pathway play critical roles in ovarian carcinogenesis in co-operation with the Akt or c-myc pathways. This first in vitro model system faithfully recapitulating the development of EOCs using normal human OSE cells should greatly facilitate further studies of EOCs.
Sasaki
Rumi
R
Virology Division, National Cancer Center Research Institute, Tokyo, Japan.
Narisawa-Saito
Mako
M
Yugawa
Takashi
T
Fujita
Masatoshi
M
Tashiro
Hironori
H
Katabuchi
Hidetaka
H
Kiyono
Tohru
T
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D043171:Chromosomal Instability; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
C530104:CCND1 protein, human; C489427:MYC protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; D051358:Cyclin-Dependent Kinase 4; C509186:TERT protein, human; D019098:Telomerase; D018631:ras Proteins