Exploiting the Complexities of Glioblastoma Stem Cells: Insights for Cancer Initiation and Therapeutic Targeting

Abstract

The discovery of glioblastoma stem cells (GSCs) in the 2000s revolutionized the cancer research field, raising new questions regarding the putative cell(s) of origin of this tumor type, and partly explaining the highly heterogeneous nature of glioblastoma (GBM). Increasing evidence has suggested that GSCs play critical roles in tumor initiation, progression, and resistance to conventional therapies. The remarkable oncogenic features of GSCs have generated significant interest in better defining and characterizing these cells and determining novel pathways driving GBM that could constitute attractive key therapeutic targets. While exciting breakthroughs have been achieved in the field, the characterization of GSCs is a challenge and the cell of origin of GBM remains controversial. For example, the use of several cell-surface molecular markers to identify and isolate GSCs has been a challenge. It is now widely accepted that none of these markers is, per se, sufficiently robust to distinguish GSCs from normal stem cells. Finding new strategies that are able to more efficiently and specifically target these niches could also prove invaluable against this devastating and therapy-insensitive tumor. In this review paper, we summarize the most relevant findings and discuss emerging concepts and open questions in the field of GSCs, some of which are, to some extent, pertinent to other cancer stem cells.

Identification of a Dexamethasone Mediated Radioprotection Mechanism Reveals New Therapeutic Vulnerabilities in Glioblastoma

“…While GBM cell lines provide vital information with regard to drug responses, it is GSCs that are thought to be the source of therapeutic resistance and tumour recurrence after surgery, and they are considered a critical target in a successful therapy approach [ 30 ]. When we analysed GSCs derived from mice overexpressing PDGFA but lacking TP53 and NF1, we found that independent of radiation the basal neurosphere formation capacity was not sensitive to sunitinib ( Figure 6 B,C).…”

The Importance of Tumor Stem Cells in Glioblastoma Resistance to Therapy

“…It is known that the heterogeneity of the tumor represents one of the main characteristics in tumorigenesis, being able to determine tumor progression and treatment resistance such as resistance to chemotherapy and radiotherapy. Indeed, tumor clones resistant to the treatments are one of the predominant causes of therapy failure and tumor recurrence [ 21 ].…”

Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation

“…Recurrent or progressive GBM usually does not respond to standard therapy, which is associated with a poor prognosis [14,15]. GSCs are a subset of cells that tolerate chemotherapy and radiotherapy and play a role in tumor recurrence [16][17][18]. Targeting GSCs and identifying new markers are the key issues involved in the development of innovative strategies to eradicate GBM [19,20].…”