C-erbB-2 or mutant Ha-ras induced malignant transformation of immortalized human ovarian surface epithelial cells in vitro
Kusakari, T.; Kariya, M.; Mandai, M.; Tsuruta, Y.; Hamid, A.A.; Fukuhara, K.; Nanbu, K.; Takakura, K.; Fujii, S.
British Journal of Cancer 89(12): 2293-2298
ISSN/ISBN: 0007-0920 PMID: 14676809 DOI: 10.1038/sj.bjc.6601423
Ovarian cancer is believed to develop from the ovarian surface epithelium through the accumulation of aberrations of oncogenes and/or tumor suppressor genes. However, it is unclear how the gene abnormalities are involved in ovarian carcinogenesis. To elucidate the process, we transfected genes reported to show their abnormalities in human ovarian cancers into human ovarian surface epithelial cells. Immortalization of the cells was achieved by the transfection of SV40 large T antigen (LT) and human telomerase reverse transcriptase (hTERT); however, the resultant cells showed no tumorigenesis. Additional transfection of either c-erbB-2 or mutant Ha-ras into the immortalized cells showed the anchorage-independent growth and tumorigenesis in mice with the incidence of 50% and 40%, respectively. Histologically, all the tumours were undifferentiated. In association with the tumorigenesis, the cells expressing c-erbB-2 or mutant Ha-ras demonstrated increased vascular endothelial growth factor secretion under hypoxia and enhanced resistance to apoptosis compared with the immortalized cells. Collectively, the introduction of either c-erbB-2 or mutant Ha-ras in the cells, which were efficiently immortalized by the transfection of LT and hTERT, showed tumorigenicity, suggesting that c-erbB-2 or mutant Ha-ras genes might be involved in ovarian carcinogenesis.