Glioblastoma stem cells: lessons from the tumor hierarchy in a lethal cancer

Abstract

Glioblastoma ranks among the most lethal of all human cancers. Glioblastomas display striking cellular heterogeneity, with stem-like glioblastoma stem cells (GSCs) at the apex. Although the original identification of GSCs dates back more than a decade, the purification and characterization of GSCs remains challenging. Despite these challenges, the evidence that GSCs play important roles in tumor growth and response to therapy has grown. Like normal stem cells, GSCs are functionally defined and distinguished from their differentiated tumor progeny at core transcriptional, epigenetic, and metabolic regulatory levels, suggesting that no single therapeutic modality will be universally effective against a heterogenous GSC population. Glioblastomas induce a systemic immunosuppression with mixed responses to oncoimmunologic modalities, suggesting the potential for augmentation of response with a deeper consideration of GSCs. Unfortunately, the GSC literature has been complicated by frequent use of inferior cell lines and a lack of proper functional analyses. Collectively, glioblastoma offers a reliable cancer to study cancer stem cells to better model the human disease and inform improved biologic understanding and design of novel therapeutics.

Targeting Glutamine Addiction in Gliomas

“…Identified for the first time in brain tumors by Singh et al, glioblastoma stem cells (GSCs) possess a capacity for proliferation, self-renewal, and differentiation [13], as well as the ability to initiate tumors in vivo [14]. Although their biology has not yet been completely unveiled, GSCs have been shown to be involved in resistance to therapies, angiogenesis, invasion, and recurrence (reviewed in [15]). The targeting of GSCs is most likely essential in order to achieve long-lasting therapeutic effects.…”

p53 drives premature neuronal differentiation in response to radiation-induced DNA damage during early neurogenesis

“…The transcriptional response of the embryonic mouse brain to radiation very much resembled that of irradiated mouse glioma which was characterized by a p53-dependent apoptotic response and a p53-independent EMT-like mechanism driving a shift from proneural to mesenchymal cells 24 . In recent years, it has been postulated that the GSCs that confer glioma treatment resistance and tumor recurrence may arise from NSCs in the adult SVZ 69 . Importantly, two new studies showed that glioblastomas –high-grade gliomas-contain (outer) radial-glia-like cells 70,71 which were hypothesized to be the cells of origin for glioblastoma development.…”

CASCADES, a novel SOX2 super-enhancer associated long noncoding RNA, regulates cancer stem cell specification and differentiation in glioblastoma multiforme

“…This pattern of relapse and progression suggests the presence of a subpopulation of cancer cells within the initial tumor that is able to survive cytotoxic therapies and drive tumor recurrence. Data from multiple studies have supported a hypothesis that the cells responsible for GBM recurrence are cancer stem cells (CSCs) (Singh et al 2004;Sanai et al 2005;Gimple et al 2019;Ma et al 2018;Lathia and Mack 2015).…”