Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin
Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin
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DOI：
10.1073/pnas.0905016106
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发表时间：
2009-10-06
影响因子：
11.1
通讯作者：
Hirao, Atsushi
中科院分区：
文献类型：
--
作者：
Tamase, Akira;Muraguchi, Teruyuki;Hirao, Atsushi
关于癌症干细胞（CSC）理论是否适用于所有肿瘤仍然存在争议。为了确定高度侵袭性实体瘤内的细胞是否是随机或分层组织的，我们将核干细胞（NS）启动子驱动GFP表达的报告系统（称为NS-GFP）与p16（Ink 4a）/p19（Arf）缺陷背景下逆转录病毒Ras表达诱导的小鼠脑肿瘤模型相结合。NS-GFP系统允许我们通过分析GFP荧光强度来监测正常神经干/前体细胞的分化过程。在荷瘤小鼠中，尽管致瘤细胞的频率非常高，但我们成功地将NS-GFP（+）细胞鉴定为肿瘤起始细胞（T-IC）。克隆研究最终确定，表型异质性可以存在于构成遗传同质性肿瘤的细胞之间，表明这种侵袭性脑肿瘤遵循CSC模型。对NS-GFP（+）脑肿瘤细胞的详细分析显示，T-IC显示出受体酪氨酸激酶c-Met的激活，其在肿瘤侵袭中起作用。因此，NS-GFP系统为阐明正常和恶性组织中的干细胞生物学提供了强有力的工具。
Controversy remains over whether the cancer stem cell (CSC) theory applies to all tumors. To determine whether cells within a highly aggressive solid tumor are stochastically or hierarchically organized, we combined a reporter system where the nucleostemin (NS) promoter drives GFP expression (termed NS-GFP) with a mouse brain tumor model induced by retroviral Ras expression on a p16(Ink4a)/p19(Arf)-deficient background. The NS-GFP system allowed us to monitor the differentiation process of normal neural stem/precursor cells by analyzing GFP fluorescence intensity. In tumor-bearing mice, despite the very high frequency of tumorigenic cells, we successfully identified the NS-GFP(+) cells as tumor-initiating cells (T-ICs). The clonal studies conclusively established that phenotypical heterogeneity can exist among the cells comprising a genetically homogeneous tumor, suggesting that this aggressive brain tumor follows the CSC model. Detailed analyses of the NS-GFP(+) brain tumor cells revealed that T-ICs showed activation of the receptor tyrosine kinase c-Met, which functions in tumor invasiveness. Thus, the NS-GFP system provides a powerful tool to elucidate stem cell biology in normal and malignant tissues.