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Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin
- Tamase, Akira, Muraguchi, Teruyuki, Naka, Kazuhito, Tanaka, Shingo, Kinoshita, Masashi, Hoshii, Takayuki, Ohmura, Masako, Shugo, Haruhiko, Ooshio, Takako, Nakada, Mitsutoshi, Sawamoto, Kazunobu, Onodera, Masafumi, Matsumoto, Kunio, Oshima, Masanobu, Asano, Masahide, Saya, Hideyuki, Okano, Hideyuki, Suda, Toshio, Hamada, Jun-ichiro, Hirao, Atsushi
- Proceedings of the National Academy of Sciences of the United States of America 2009 v.106 no.40 pp. 17163-17168
- brain, fluorescence, hepatocyte growth factor receptor, mice, models, neoplasm cells, neoplasms, stem cells
- 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 p16Ink⁴a/p19Arf-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.