RRC ID 48885
Author Sasaki R, Narisawa-Saito M, Yugawa T, Fujita M, Tashiro H, Katabuchi H, Kiyono T.
Title Oncogenic transformation of human ovarian surface epithelial cells with defined cellular oncogenes.
Journal Carcinogenesis
Abstract 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.
Volume 30(3)
Pages 423-31
Published 2009-3-1
DOI 10.1093/carcin/bgp007
PII bgp007
PMID 19126650
MeSH Animals Cell Transformation, Neoplastic / metabolism* Cell Transformation, Neoplastic / pathology Cells, Cultured Chromosomal Instability Cyclin D1 / biosynthesis Cyclin D1 / genetics Cyclin-Dependent Kinase 4 / biosynthesis Cyclin-Dependent Kinase 4 / genetics Epithelial Cells / metabolism* Epithelial Cells / pathology Female Humans Mice Mice, Inbred BALB C Mice, Nude Mutation Oncogenes* Ovarian Neoplasms / metabolism* Ovarian Neoplasms / pathology Ovary / metabolism Ovary / pathology Proto-Oncogene Proteins c-akt / genetics Proto-Oncogene Proteins c-akt / metabolism Proto-Oncogene Proteins c-bcl-2 / genetics Proto-Oncogene Proteins c-bcl-2 / metabolism Proto-Oncogene Proteins c-myc / genetics Proto-Oncogene Proteins c-myc / metabolism Telomerase / biosynthesis Telomerase / genetics Transduction, Genetic Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism ras Proteins / genetics ras Proteins / metabolism
IF 4.603
Times Cited 66
DNA material CSII-CMV-RfA (RDB04386) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394).