Transient depletion of p53 followed by transduction of c-Myc and K-Ras converts ovarian stem-like cells into tumor-initiating cells
Transient depletion of p53 followed by transduction of c-Myc and K-Ras converts ovarian stem-like cells into tumor-initiating cells
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DOI：
10.1093/carcin/bgr183
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发表时间：
2011-11-01
期刊：
影响因子：
4.7
通讯作者：
Nagano, Osamu
中科院分区：
文献类型：
--
作者：
Motohara, Takeshi;Masuko, Sachiko;Nagano, Osamu
虽然在几种类型的人类癌症中存在肿瘤起始细胞（T-IC），但体干细胞对T-IC发育的贡献仍不清楚。在这里，我们表明，正常小鼠卵巢含有上皮细胞粘附分子（EpCAM）表达干细胞样细胞，具有分化成细胞角蛋白8（CK 8）表达上皮细胞的后代细胞的能力。此外，在表达EpCAM的卵巢干细胞样细胞中，RNA干扰介导的肿瘤抑制因子p53的瞬时消耗，随后逆转录病毒介导的c-Myc和K-Ras癌基因的转移导致卵巢T-IC的产生。已建立的卵巢T-IC在体内产生了分层组织的致死性肿瘤，并能够进行腹膜转移。最后，随后的RNA干扰介导的肿瘤细胞中p53的敲低触发了表达EpCAM的干细胞样肿瘤细胞的扩增并诱导了进一步的肿瘤生长。这些数据揭示了p53在卵巢干细胞样肿瘤细胞的发展和扩增以及随后的恶性进展中的作用。
Although the existence of tumor-initiating cells (T-ICs) in several types of human cancer has been documented, the contribution of somatic stem cells to the development of T-ICs has remained unclear. Here, we show that normal mouse ovary contains epithelial cell adhesion molecule (EpCAM)-expressing stem-like cells that possess the ability to differentiate into cytokeratin 8 (CK8)-expressing epithelial progeny cells. Furthermore, RNA interference-mediated transient depletion of the tumor suppressor p53 followed by retrovirus-mediated transfer of c-Myc and K-Ras oncogenes in EpCAM-expressing ovarian stem-like cells resulted in the generation of ovarian T-ICs. The established ovarian T-ICs gave rise to hierarchically organized lethal tumors in vivo and were able to undergo peritoneal metastasis. Finally, subsequent RNA interference-mediated knockdown of p53 in tumor cells triggered the expansion of EpCAM-expressing stem-like tumor cells and induced further tumor growth. These data reveal a role for p53 in the development and expansion of ovarian stem-like tumor cells and subsequent malignant progression.