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

Research output: Contribution to journalArticle

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

Fingerprint

Glioblastoma
Glioma
Brain Neoplasms
Stem Cells
Down-Regulation
Neural Stem Cells
Penetrance
Astrocytoma
Neoplasms
Transcription Factors
Animal Models
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Muraguchi, T., Tanaka, S., Yamada, D., Tamase, A., Nakada, M., Nakamura, H., ... 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

NKX2.2 suppresses self-renewal of glioma-initiating cells. / Muraguchi, Teruyuki; Tanaka, Shingo; Yamada, Daisuke; Tamase, Akira; Nakada, Mitsutoshi; Nakamura, Hideo; Hoshii, Takayuki; Ooshio, Takako; Tadokoro, Yuko; Naka, Kazuhito; Ino, Yasushi; Todo, Tomoki; Kuratsu, Jun Ichi; Saya, Hideyuki; Hamada, Jun Ichiro; Hirao, Atsushi.

In: Cancer Research, Vol. 71, No. 3, 01.02.2011, p. 1135-1145.

Research output: Contribution to journalArticle

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, JI, Saya, H, Hamada, JI & Hirao, A 2011, 'NKX2.2 suppresses self-renewal of glioma-initiating cells', Cancer Research, vol. 71, no. 3, pp. 1135-1145. https://doi.org/10.1158/0008-5472.CAN-10-2304
Muraguchi T, Tanaka S, Yamada D, Tamase A, Nakada M, Nakamura H et al. NKX2.2 suppresses self-renewal of glioma-initiating cells. Cancer Research. 2011 Feb 1;71(3):1135-1145. https://doi.org/10.1158/0008-5472.CAN-10-2304
Muraguchi, Teruyuki ; Tanaka, Shingo ; Yamada, Daisuke ; Tamase, Akira ; Nakada, Mitsutoshi ; Nakamura, Hideo ; Hoshii, Takayuki ; Ooshio, Takako ; Tadokoro, Yuko ; Naka, Kazuhito ; Ino, Yasushi ; Todo, Tomoki ; Kuratsu, Jun Ichi ; Saya, Hideyuki ; Hamada, Jun Ichiro ; Hirao, Atsushi. / NKX2.2 suppresses self-renewal of glioma-initiating cells. In: Cancer Research. 2011 ; Vol. 71, No. 3. pp. 1135-1145.
@article{5a59b94c15f24bf89e4a3dbcd3333c21,
title = "NKX2.2 suppresses self-renewal of glioma-initiating cells",
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.",
author = "Teruyuki Muraguchi and Shingo Tanaka and Daisuke Yamada and Akira Tamase and Mitsutoshi Nakada and Hideo Nakamura and Takayuki Hoshii and Takako Ooshio and Yuko Tadokoro and Kazuhito Naka and Yasushi Ino and Tomoki Todo and Kuratsu, {Jun Ichi} and Hideyuki Saya and Hamada, {Jun Ichiro} and Atsushi Hirao",
year = "2011",
month = "2",
day = "1",
doi = "10.1158/0008-5472.CAN-10-2304",
language = "English",
volume = "71",
pages = "1135--1145",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

TY - JOUR

T1 - NKX2.2 suppresses self-renewal of glioma-initiating cells

AU - Muraguchi, Teruyuki

AU - Tanaka, Shingo

AU - Yamada, Daisuke

AU - Tamase, Akira

AU - Nakada, Mitsutoshi

AU - Nakamura, Hideo

AU - Hoshii, Takayuki

AU - Ooshio, Takako

AU - Tadokoro, Yuko

AU - Naka, Kazuhito

AU - Ino, Yasushi

AU - Todo, Tomoki

AU - Kuratsu, Jun Ichi

AU - Saya, Hideyuki

AU - Hamada, Jun Ichiro

AU - Hirao, Atsushi

PY - 2011/2/1

Y1 - 2011/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79551572113&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79551572113&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-10-2304

DO - 10.1158/0008-5472.CAN-10-2304

M3 - Article

C2 - 21169405

AN - SCOPUS:79551572113

VL - 71

SP - 1135

EP - 1145

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 3

ER -