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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.