NKX2.2 Suppresses Self-Renewal of Glioma-Initiating Cells

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

doi:10.1158/0008-5472.can-10-2304

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 p16(Ink4a)/p19(Arf) 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.

Highlights

Glioblastoma (GBM) is the most common high-grade malignant glioma in humans and is categorized as a WHO grade IV glioma, a highly aggressive, invasive, and destructive brain tumor [1]
We report that Nkx2.2 is a critical factor controlling self-renewal of glioma-initiating cells (GIC), an activity conserved in human GICs
Because Ras signaling is a major pathway upregulated in gliomagenesis, we asked whether Ras activation in Neural stem/ progenitor cell (NPC) could induce gliomagenesis in vivo

Summary

Introduction

Glioblastoma (GBM) is the most common high-grade malignant glioma in humans and is categorized as a WHO grade IV glioma, a highly aggressive, invasive, and destructive brain tumor [1]. There are 2 GBM subtypes, primary and secondary, which are distinguished by clinical characteristics. Primary GBM arises de novo in the absence of a preexisting low-grade lesion, whereas secondary GBM develops progressively (over 5–10 years) from lower grade gliomas such as Authors' Affiliations: 1Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute and 2Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan; 3Department of Neurosurgery, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University Graduate School, Kumamoto, Japan; 4Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi, Saitama, Japan; 5Department of Neurosurgery and Translational Research Center, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and 6Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan. These pathways include the receptor tyrosine kinase (RTK)/RAS/ PI3K pathway (including EGFR, PDGFR, NF1, and PTEN); the p53 pathway (including TP53, CDKN2A/p14ARF, and MDM2); and the RB pathway (including RB1, CDKN2A/p16INK4A, CDKN2B and CDKN2C; refs. 1, 2)

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