Abstract
Glioblastoma multiforme (GBM), an aggressive brain tumor of astrocytic/neural stem cell origin, represents one of the most incurable cancers. GBM tumors are highly heterogeneous. However, most tumors contain a subpopulation of cells that display neural stem cell characteristics in vitro and that can generate a new brain tumor upon transplantation in mice. Hence, previously identified molecular pathways regulating neural stem cell biology were found to represent the cornerstone of GBM stem cell self-renewal mechanism. GBM tumors are also notorious for their resistance to radiation therapy. Notably, GBM “cancer stem cells” were also found to be responsible for this radioresistance. Herein, we will analyze the data supporting or not the cancer stem cell model in GBM, overview the current knowledge regarding GBM stem cell self-renewal and radioresistance molecular mechanisms, and discuss the potential therapeutic application of these findings.
Highlights
Glioblastoma multiforme (GBM), a grade III or IV malignant astrocytoma as classified by the world health organization, is the most common and lethal primary brain tumor in adults [1]
An overwhelming amount of literature favors the concept that brain tumor initiating cells in GBM arise from the transformation of cells residing in the subventricular zone (SVZ) of the cerebral cortex rather than from parenchymal astrocytes— the later possibility cannot be excluded for all GBM cases
Using INK4A/ARFnull human GBM specimens, we showed that BMI1 is enriched in CD133+ cells and required to sustain their self-renewal through prevention of CD133+ cells apoptosis and/or differentiation into neurons and astrocytes [70]
Summary
Glioblastoma multiforme (GBM), a grade III or IV malignant astrocytoma as classified by the world health organization, is the most common and lethal primary brain tumor in adults [1]. Current therapies offered to patients include maximal exeresis, combined radio- and chemotherapy, and adjuvant chemotherapy [2,3]. Even with these multiple interventions, the prognosis has improved minimally during the last decades. GBM is a heterogeneous brain tumor comprising a fraction of cells that resemble in their gene expression profile and phenotypic characteristics adult neural stem cells (NSCs) found in the brain. GBM classification includes expression of the glial fibrillary acidic protein (GFAP) in cancer cells, a marker of astrocytes and NSCs. An overwhelming amount of literature favors the concept that brain tumor initiating cells in GBM arise from the transformation of cells residing in the subventricular zone (SVZ) of the cerebral cortex (the adult neural stem cell niche) rather than from parenchymal astrocytes— the later possibility cannot be excluded for all GBM cases. Understanding the mechanisms governing NSCs self-renewal could bring critical insight as to how GBM tumors grow and survive, providing potentially new therapeutic strategies against this highly lethal disease
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