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.

Contribution of Tumor Heterogeneity in a New Animal Model of CNS Tumors

“…We also found that transient expression of Ngn2 (by a non-donor episomal plasmid) in radial glia was sufficient to produce ATRT like tumors. The effectiveness of transient Ngn2 expression, in combination with previous findings that Ngn2 or NeuroD1 expressed in glioma cells induces cell death and neuronal differentiation without changing tumor type (46, 47) supports the idea that Ngn2 and NeuroD1 acts in early stage radial progenitors to change the type of tumor generated. We have co-expressed Ngn2 with GFAP donor plasmids and found the resulted tumors were similar to tumors induced by GFAP donor plasmids alone.…”

Role of the microtubule-targeting drug vinflunine on cell-cell adhesions in bladder epithelial tumour cells

“…This approach is based on the concept that cancer cells arise from tissue stem cells and share the stemness and plasticity with normal stem cells. Differentiation therapy aims to induce cancer cells to differentiate by treatment with differentiation-inducing agents [46,47]. Most of the differentiation agents can inhibit proliferation and induce cells to differentiate and then undergo apoptosis [48,49].…”

C-Glycoside Mimetics Inhibit Glioma Stem Cell Proliferation, Migration, and Invasion

“…27 SNB 75 displays prominent mesenchymal features, 28 while Gli4 and Gli7 express proneural characteristics. 18 However, both 5.3d and 3.2a (data not shown) inhibit Gli4 and GLi7 invasion capacity with the same efficiency.…”