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Carcinogenesis Advance Access originally published online on January 6, 2009
Carcinogenesis 2009 30(3):423-431; doi:10.1093/carcin/bgp007
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Oncogenic transformation of human ovarian surface epithelial cells with defined cellular oncogenes

Rumi Sasaki1,2, Mako Narisawa-Saito1, Takashi Yugawa1, Masatoshi Fujita1, Hironori Tashiro2, Hidetaka Katabuchi2 and Tohru Kiyono1,*

1 Virology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
2 Department of Gynecology, Faculty of Medical and Pharmaceutical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto-City, Kumamoto 860-8556, Japan

* To whom correspondence should be addressed. Tel: +81 3 3542 2511; Fax: +81 3 3543 2181; Email: tkiyono{at}ncc.go.jp

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.

Abbreviations: Cdk, cyclin-dependent kinase; EOC, epithelial ovarian carcinoma; HPV, human papillomavirus; hTERT, human telomerase reverse transcriptase; OSE, ovarian surface epithelium; SCID, severely compromised immunodeficient; shRNA, short hairpin RNA

Received October 11, 2008; revised December 11, 2008; accepted December 22, 2008.


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