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Cell death and neuronal differentiation of glioblastoma stem‐like cells induced by neurogenic transcription factors
Author(s) -
Guichet PierreOlivier,
Bieche Ivan,
Teigell Marisa,
Serguera Ché,
Rothhut Bernard,
Rigau Valérie,
Scamps Frédérique,
Ripoll Chantal,
Vacher Sophie,
Taviaux Sylvie,
Chevassus Hugues,
Duffau Hugues,
Mallet Jacques,
Susini Aurélie,
Joubert Dominique,
Bauchet Luc,
Hugnot JeanPhilippe
Publication year - 2013
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.22429
Subject(s) - biology , sox2 , neurosphere , stem cell , microbiology and biotechnology , glioma , downregulation and upregulation , cancer research , olig2 , cellular differentiation , nestin , stem cell marker , neural stem cell , transcription factor , immunology , adult stem cell , neuroscience , oligodendrocyte , central nervous system , gene , genetics , myelin
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. © 2012 Wiley Periodicals, Inc.