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Review
. 2019 Jun 1;33(11-12):591-609.
doi: 10.1101/gad.324301.119.

Glioblastoma Stem Cells: Lessons From the Tumor Hierarchy in a Lethal Cancer

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Free PMC article
Review

Glioblastoma Stem Cells: Lessons From the Tumor Hierarchy in a Lethal Cancer

Ryan C Gimple et al. Genes Dev. .
Free PMC article

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.

Keywords: brain tumor; cancer stem cell; glioblastoma; glioblastoma stem cell; tumor-initiating cell.

Figures

Figure 1.
Figure 1.
GSC definition and key features. (A) GSCs are defined by a series of functional criteria, including tumor-initiating capacity following serial transplantation, self-renewal, and the ability to recapitulate tumor heterogeneity. (B) GSCs may arise from neural stem cells or transformed astrocytes that gain access to stem-specific transcriptional programs. (C) GSCs display cellular and phenotypic heterogeneity dependent on anatomic location within the tumor and distinct microenvironmental cues. (D) The GSC model allows for hierarchical rigidity and plasticity models.
Figure 2.
Figure 2.
Epigenetic and posttranscriptional regulation of GSCs. (A) Critical epigenetic regulators drive GSC maintenance and response to external cues by regulating gene expression programs. (2-HG) (R)-2-hydroxyglutarate; (N6-mA) N6-methyladenine; (5mC) 5-methylcytosine; (K27-ac) acetylation of histone 3 on Lys27; (K27-me) methylation of histone 3 on Lys27; (K119-ub) ubiquitination of histone 2A on Lys119. (B) Transcriptional regulators and posttranscriptional processes modify gene expression to support GSCs. (m6A) N6-methyladenosine.
Figure 3.
Figure 3.
Multiple metabolic pathways power GSCs. GSCs depend on key enzymes to support their bioenergetic needs, requirements for proliferative and epigenetic substrates, and capacity to adapt to harsh microenvironments. (Ox. Phos) Oxidative phosphorylation; (TCA) tricarboxylic acid cycle.
Figure 4.
Figure 4.
GSCs in context. Microenvironmental interactions with other tumor cells, neurons, macrophages, T cells, and the vasculature are key for supporting GSCs.
Figure 5.
Figure 5.
Targeting GSCs. Numerous avenues exist for targeting GSCs, including selectively poisoning epigenetic, metabolic, microenvironmental, posttranscriptional, and immune interactions.

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