Oncogenic transformation of human ovarian surface epithelial cells with defined cellular oncogenes
Oncogenic transformation of human ovarian surface epithelial cells with defined cellular oncogenes
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DOI：
10.1093/carcin/bgp007
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发表时间：
2009-03-01
期刊：
影响因子：
4.7
通讯作者：
Kiyono, Tohru
中科院分区：
文献类型：
--
作者：
Sasaki, Rumi;Narisawa-Saito, Mako;Kiyono, Tohru
卵巢表面上皮（OSE）被认为是引起上皮性卵巢癌（EOCs）的原因。为了阐明从OSE发展EOC的早期过程，用非病毒人基因（突变Cdk 4、cyclinD 1和hTERT）转导两批原代人OSE细胞，以便有效地建立没有染色体不稳定性的正常二倍体OSE细胞。然后将在EOC中经常观察到的定义的遗传改变转导到OSE细胞中。p53失活和致癌Kras转导的组合并没有赋予免疫缺陷小鼠肿瘤形成的能力，尽管Akt的额外转导或c-myc与bcl-2的组合转导确实导致肿瘤形成。在后一种情况下，肿瘤表现出令人联想到人类EOC的表型，包括细胞角蛋白表达、高度侵袭性表型、转移行为和腹水形成。这些结果表明，p53的失活和Ras通路的激活与Akt或c-myc通路的协同作用在卵巢癌的发生中起关键作用。这第一个在体外模型系统忠实地重演的发展EOCs使用正常人OSE细胞应大大促进EOCs的进一步研究。
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.