Cancer stem cell hypothesis 2.0 in glioblastoma: Where are we now and where are we going?

Abstract

Over the past 2 decades, the cancer stem cell (CSC) hypothesis has provided insight into many malignant tumors, including glioblastoma (GBM). Cancer stem cells have been identified in patient-derived tumors and in some mouse models, allowing for a deeper understanding of cellular and molecular mechanisms underlying GBM growth and therapeutic resistance. The CSC hypothesis has been the cornerstone of cellular heterogeneity, providing a conceptual and technical framework to explain this longstanding phenotype in GBM. This hypothesis has evolved to fit recent insights into how cellular plasticity drives tumor growth to suggest that CSCs do not represent a distinct population but rather a cellular state with substantial plasticity that can be achieved by non-CSCs under specific conditions. This has further been reinforced by advances in genomics, including single-cell approaches, that have used the CSC hypothesis to identify multiple putative CSC states with unique properties, including specific developmental and metabolic programs. In this review, we provide a historical perspective on the CSC hypothesis and its recent evolution, with a focus on key functional phenotypes, and provide an update on the definition for its use in future genomic studies.

Keywords: cancer stem cell; glioblastoma; heterogeneity; proliferation.

Figure 1.

Summary of nomenclatures derived from scRNA-seq studies of GBM. Each panel represents a graphical summary of transcriptional states proposed by different research groups. The circles represent individual cells arranged in an idealized 2-dimensional representation. Proposed transcriptional states are represented in different colors. All transcriptional states are here arranged along an axis that has neural progenitor-like characteristics at one end and mesenchymal-like characteristics at the other.

Figure 2.

Proposed mechanisms for cell state transitions. (A) In one model, mesenchymal-like and neural-like CSCs produce independent lineages. (B) Alternatively, mesenchymal-like CSC are slow cycling and the most self-renewing cell state. They can give rise to neural-like CSCs and therefore can recapitulate the full extent of cellular heterogeneity in GBM. (C) In the third model, mesenchymal-like and neural-like CSCs are functionally equivalent and can interconvert depending on their niche, that is, their state is specified by their specific microenvironment.

Figure 3.

Regulation of the quiescent stem cell state. Patient-derived xenograft and genetic mouse studies have demonstrated that both cell-intrinsic and cell-extrinsic mechanisms, many of which have previously been suggested to regulate the overall CSC phenotype, regulate the quiescent CSC state. Cell-intrinsic regulators include cell lineage, tumor subtype, and cell cycle properties; cell extrinsic regulators include intratumoral spatial location, cell–cell interactions, and the GBM TME.