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 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.
authors.affiliation: Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Muraguchi
authors.forename: Shingo
authors.initials: S
authors.lastname: Tanaka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamada
authors.forename: Akira
authors.initials: A
authors.lastname: Tamase
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Nakada
authors.forename: Hideo
authors.initials: H
authors.lastname: Nakamura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hoshii
authors.forename: Takako
authors.initials: T
authors.lastname: Ooshio
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tadokoro
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Naka
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ino
authors.forename: Tomoki
authors.initials: T
authors.lastname: Todo
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kuratsu
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Hamada
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D029961:Zebrafish Proteins
chemical_list: D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C000715631:NKX2-2 protein, human; C000715627:Nkx2-2 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish