NKX2.2 suppresses self-renewal of glioma-initiating cells

Teruyuki Muraguchi, Shingo Tanaka, Daisuke Yamada, Akira Tamase, Mitsutoshi Nakada, Hideo Nakamura, Takayuki Hoshii, Takako Ooshio, Yuko Tadokoro, Kazuhito Naka, Yasushi Ino, Tomoki Todo, Jun Ichi Kuratsu, Hideyuki Saya, Jun Ichiro Hamada, Atsushi Hirao

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17 Citations (Scopus)

Abstract

Glioblastoma (GBM) is the most aggressive and destructive form of brain cancer. Animal models that can unravel the mechanisms underlying its progression are needed to develop rational and effective molecular therapeutic approaches. In this study, we report the development of mouse models for spontaneous gliomas representing distinct progressive stages of disease that are governed by defined genetic alterations. Neural stem/ progenitor cell (NPC)-specific constitutive Ras activation in vivo plus p53 deficiency led to development of primarily anaplastic astrocytoma (grade III), whereas combined loss of p53 plus p16Ink4a/p19Arf led to development of GBM (grade IV) at 100% penetrance within 6 weeks. These glioma models showed enhanced stem cell properties (stemness) accompanied by malignant progression. Notably, we determined that, in our models and in human specimens, downregulation of the homeodomain transcription factor NKX2.2, which is essential for oligodendroglial differentiation, was correlated with increased tumor malignancy. NKX2.2 overexpression by GBM-derived glioma-initiating cells (GIC) induced oligodendroglial differentiation and suppressed self-renewal capacity. By contrast, Nkx2.2 downregulation in mouse NPCs accelerated GBM formation. Importantly, the inhibitory effects of NXK2.2 on GIC self-renewal were conserved in human cells. Thus, our mouse models offer pathobiologically significant advantages to investigate the nature of brain tumors, with improved opportunities to develop novel mechanism-based therapeutic approaches.

Original languageEnglish
Pages (from-to)1135-1145
Number of pages11
JournalCancer Research
Volume71
Issue number3
DOIs
Publication statusPublished - 2011 Feb 1

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Muraguchi, T., Tanaka, S., Yamada, D., Tamase, A., Nakada, M., Nakamura, H., Hoshii, T., Ooshio, T., Tadokoro, Y., Naka, K., Ino, Y., Todo, T., Kuratsu, J. I., Saya, H., Hamada, J. I., & Hirao, A. (2011). NKX2.2 suppresses self-renewal of glioma-initiating cells. Cancer Research, 71(3), 1135-1145. https://doi.org/10.1158/0008-5472.CAN-10-2304