Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin

Akira Tamase, Teruyuki Muraguchi, Kazuhito Naka, Shingo Tanaka, Masashi Kinoshita, Takayuki Hoshii, Masako Ohmura, Haruhiko Shugo, Takako Ooshio, Mitsutoshi Nakada, Kazunobu Sawamoto, Masafumi Onodera, Kunio Matsumoto, Masanobu Oshima, Masahide Asano, Hideyuki Saya, Hideyuki Okano, Toshio Suda, Jun Ichiro Hamada, Atsushi Hirao

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

Abstract

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/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 tumorinitiating 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.

Original languageEnglish
Pages (from-to)17163-17168
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number40
DOIs
Publication statusPublished - 2009 Oct 6

Keywords

  • Cancer stem cell
  • Invasion

ASJC Scopus subject areas

  • General

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