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Review
. 2021 Feb 25;23(2):199-213.
doi: 10.1093/neuonc/noaa259.

The evolution of the cancer stem cell state in glioblastoma: emerging insights into the next generation of functional interactions

Kelly Mitchell  1   2 , Katie Troike  1   3 , Daniel J Silver  1 , Justin D Lathia  1   4
Affiliations
Review

The evolution of the cancer stem cell state in glioblastoma: emerging insights into the next generation of functional interactions

Kelly Mitchell et al. Neuro Oncol. .

Abstract

Cellular heterogeneity is a hallmark of advanced cancers and has been ascribed in part to a population of self-renewing, therapeutically resistant cancer stem cells (CSCs). Glioblastoma (GBM), the most common primary malignant brain tumor, has served as a platform for the study of CSCs. In addition to illustrating the complexities of CSC biology, these investigations have led to a deeper understanding of GBM pathogenesis, revealed novel therapeutic targets, and driven innovation towards the development of next-generation therapies. While there continues to be an expansion in our knowledge of how CSCs contribute to GBM progression, opportunities have emerged to revisit this conceptual framework. In this review, we will summarize the current state of CSCs in GBM using key concepts of evolution as a paradigm (variation, inheritance, selection, and time) to describe how the CSC state is subject to alterations of cell intrinsic and extrinsic interactions that shape their evolutionarily trajectory. We identify emerging areas for future consideration, including appreciating CSCs as a cell state that is subject to plasticity, as opposed to a discrete population. These future considerations will not only have an impact on our understanding of this ever-expanding field but will also provide an opportunity to inform future therapies to effectively treat this complex and devastating disease.

Keywords: cancer stem cell; glioblastoma; review; stem cell state.

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Figures

Fig. 1
Fig. 1
Described mechanisms of therapeutic resistance in GBM CSCs. Several studies have ascribed therapy resistance to features of GBM CSCs that prevent or antagonize the effects of these therapies. For instance, slowly dividing/quiescent GBM cells, which exhibit higher tumor initiating frequency, were resistant to radiation and chemotherapy.,, In addition, CD133+ GBM cells express higher levels of drug efflux transporters such as ABCG2, ABCC1, and ABCC3, and also highly express DNA repair enzymes such as MGMT.,,, In addition, several pathways, processes and cellular states have been linked to radiation resistance. For instance, CD133+ GBM cells express higher levels of autophagy related proteins LC3, ATG5, and ATG12, radiation specifically prompted LC3-II expression in CD133+ GBM cells, and inhibition of autophagy sensitized cells to radiation. Inhibition of the gap junction protein connexin-46 or -43 sensitized TMZ resistant cells to TMZ-mediated apoptosis., Activation of the Wnt and Notch pathways have been described in radioresistant GBM CSCs, and radiosensitization could be achieved by inhibiting Wnt signaling or with gamma secretase inhibitors, which target the Notch pathway., In a similar manner to Notch, genetic targeting of receptor tyrosine kinase c-Met or its ligand sensitized cells to TMZ. Furthermore, primary patient-derived GBM CSCs with mesenchymal-like gene expression profiles were radioresistant, and radiation induced a proneural to mesenchymal gene expression profile in GBM cells,, suggesting an enrichment or expansion of the resistant cells upon treatment. Knockdown of the master regulator of the epithelial to mesenchymal transition, ZEB1, sensitized GBM CSCs to chemotherapy through reducing expression of MGMT and c-MYB.
Fig. 2
Fig. 2
CSC nutrient metabolism. CSC plasticity is further demonstrated by the ability of these cells to alter substrate utilization as an adaptive advantage in states of limited nutrient availability. In the context of glucose metabolism, the Warburg effect, as well as oxidative phosphorylation, have been shown to contribute to the CSC phenotype. CSCs can also scavenge glucose from nutrient-poor environments by upregulating surface expression of glucose transporters. Additionally, investigation into lipid metabolism in these cells has revealed an important role for fatty acid oxidation and lipid uptake in CSC proliferation and maintenance. Amino acid metabolism in GBM CSCs is an emerging area of study but existing data provide evidence for the importance of glutamine, asparagine, and branched chain amino acid metabolism in regulating the stem cell state.
Fig. 3
Fig. 3
Immune modulation by CSCs. CSCs can alter tumor-associated immunity by secretion of factors that directly and indirectly suppress immune responses. For instance, several factors secreted by CSCs recruit TAMs, which subsequently suppress adaptive immune responses. Some factors have been found to inhibit natural killer cell and dendritic cell responses. CSC-derived factors can also directly affect T cell responses, leading to expansion of regulatory T cells or inhibition of cytotoxic T cells. Effects of specific cytokines are described in more detail in Table 2.
Fig. 4
Fig. 4
Several phenomena underlie the CSC state and warrant further exploration. The CSC state is shaped by cell intrinsic alterations and cell extrinsic interactions that contribute to clonal evolution and heterogeneity in GBM. Well-studied, established aspects of CSCs in GBM include genetic alterations, self-renewal signaling, tumor initiation potential, and therapeutic resistance (represented above the water). Several emerging areas likely affecting the CSC state include vast epigenetic changes, metabolic alterations, drivers of invasion, the role of immune and neural cell interactions, and sex differences (below the water). CSCs must be considered in the context of all of these features and interactions.
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