title: Cell death and neuronal differentiation of glioblastoma stem-like cells induced by neurogenic transcription factors.
abstract: Glioblastoma multiform (GBM) are devastating brain tumors containing a fraction of multipotent stem-like cells which are highly tumorigenic. These cells are resistant to treatments and are likely to be responsible for tumor recurrence. One approach to eliminate GBM stem-like cells would be to force their terminal differentiation. During development, neurons formation is controlled by neurogenic transcription factors such as Ngn1/2 and NeuroD1. We found that in comparison with oligodendrogenic genes, the expression of these neurogenic genes is low or absent in GBM tumors and derived cultures. We thus explored the effect of overexpressing these neurogenic genes in three CD133(+) Sox2(+) GBM stem-like cell cultures and the U87 glioma line. Introduction of Ngn2 in CD133(+) cultures induced massive cell death, proliferation arrest and a drastic reduction of neurosphere formation. Similar effects were observed with NeuroD1. Importantly, Ngn2 effects were accompanied by the downregulation of Olig2, Myc, Shh and upregulation of Dcx and NeuroD1 expression. The few surviving cells adopted a typical neuronal morphology and some of them generated action potentials. These cells appeared to be produced at the expense of GFAP(+) cells which were radically reduced after differentiation with Ngn2. In vivo, Ngn2-expressing cells were unable to form orthotopic tumors. In the U87 glioma line, Ngn2 could not induce neuronal differentiation although proliferation in vitro and tumoral growth in vivo were strongly reduced. By inducing cell death, cell cycle arrest or differentiation, this work supports further exploration of neurogenic proteins to oppose GBM stem-like and non-stem-like cell growth.
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Hôpital St Eloi, 80 av Augustin, Fliche 34091, Montpellier, Cedex 05, France. pierre-olivier.guichet@inserm.fr
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Guichet
authors.forename: Ivan
authors.initials: I
authors.lastname: Bieche
authors.forename: Marisa
authors.initials: M
authors.lastname: Teigell
authors.forename: Ché
authors.initials: C
authors.lastname: Serguera
authors.forename: Bernard
authors.initials: B
authors.lastname: Rothhut
authors.forename: Valérie
authors.initials: V
authors.lastname: Rigau
authors.forename: Frédérique
authors.initials: F
authors.lastname: Scamps
authors.forename: Chantal
authors.initials: C
authors.lastname: Ripoll
authors.forename: Sophie
authors.initials: S
authors.lastname: Vacher
authors.forename: Sylvie
authors.initials: S
authors.lastname: Taviaux
authors.forename: Hugues
authors.initials: H
authors.lastname: Chevassus
authors.forename: Hugues
authors.initials: H
authors.lastname: Duffau
authors.forename: Jacques
authors.initials: J
authors.lastname: Mallet
authors.forename: Aurélie
authors.initials: A
authors.lastname: Susini
authors.forename: Dominique
authors.initials: D
authors.lastname: Joubert
authors.forename: Luc
authors.initials: L
authors.lastname: Bauchet
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Hugnot
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology*; D016923:Cell Death; D002454:Cell Differentiation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005909:Glioblastoma / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000494:pharmacology; D000076104:Oligodendrocyte Transcription Factor 2; D016274:Oncogene Protein p55(v-myc) / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D014157:Transcription Factors / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D016274:Oncogene Protein p55(v-myc); D010455:Peptides; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; C093970:NEUROD1 protein, human; C105389:NEUROG1 protein, human; C405708:OLIG2 protein, human; C000606023:PROM1 protein, human; C509239:SHH protein, human; C527782:SOX2 protein, human