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

Abstract

Cellular heterogeneity is a hallmark of advanced cancers and has been ascribed to a population of self-renewing, therapeutically resistant cancer stem cells (CSCs). Glioblastoma (GBM), the most common primary malignant brain tumor, has been a paradigm for the study of CSCs and has helped to define key aspects of the disease as well as served as the basis for 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 moving beyond a single CSC population to appreciate 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 target this complex and devastating disease.

Effects of the Anti-Tumorigenic Agent AT101 on Human Glioblastoma Cells in the Microenvironmental Glioma Stem Cell Niche

“…The dismal prognosis of GBMs is largely attributed to the heterogeneous nature of this highly malignant brain tumor. Here, heterogeneity among different tumor cells arises within a single tumor as a result of intrinsic molecular and genetic changes and is also influenced by the microenvironmental niche in which the GBM cells reside [ 6 , 9 ]. Interactions between specialized tumor cell subpopulations and their environment through autocrine or paracrine factors promote invasion and growth of the tumor cells and affect their response to therapy [ 9 , 40 ].…”

“…Here, heterogeneity among different tumor cells arises within a single tumor as a result of intrinsic molecular and genetic changes and is also influenced by the microenvironmental niche in which the GBM cells reside [ 6 , 9 ]. Interactions between specialized tumor cell subpopulations and their environment through autocrine or paracrine factors promote invasion and growth of the tumor cells and affect their response to therapy [ 9 , 40 ]. Besides several stromal cells (endothelial cells, immune cells, and other parenchymal cells) and more differentiated GBM cells, GBM stem cells are major key players within the development of tumor recurrence and treatment sensitivity [ 6 , 9 , 40 ].…”

“…Interactions between specialized tumor cell subpopulations and their environment through autocrine or paracrine factors promote invasion and growth of the tumor cells and affect their response to therapy [ 9 , 40 ]. Besides several stromal cells (endothelial cells, immune cells, and other parenchymal cells) and more differentiated GBM cells, GBM stem cells are major key players within the development of tumor recurrence and treatment sensitivity [ 6 , 9 , 40 ]. Thus, an urgent need exists to develop alternative, more effective treatment strategies.…”

“…AT101 is able to trigger autophagic, mitophagic, or apoptotic cell death by versatile mechanisms of action as the inhibition of Bcl-2 proteins, the induction of mitochondrial dysfunction, or by modulating serval signaling pathways in a specific manner [ 22 , 23 , 24 , 25 , 26 , 41 ]. Moreover, since it is known that AT101 is able to suppress the growth of glioma stem cells [ 28 , 29 ], AT101 seems to be a promising chemotherapeutic agent to prevent GBM recurrences, which often arise from dysfunctional (tumor) stem cells [ 6 , 9 , 40 ]. However, to date, the influence of the GBM stem cell microenvironment on the AT101 responsiveness of native, non-stem GBM cells is not known.…”

“…One major reason for this resistance is the pronounced intra- and intertumoral heterogeneity of GBMs [ 2 , 3 ]. Based on various genetically determined morphological properties and protein expression patterns [ 4 ], as well as on microenvironmental features like the contribution of different stromal cells [ 5 , 6 ], evolutionary processes within the heterogeneous tumor mass give rise to specialized tumor cell subpopulations (e.g., GBM tumor stem cells, more differentiated GBM cells or fast proliferating or migrating ones) [ 7 , 8 , 9 ]. The different tumor cell subpopulations communicate either directly or indirectly with e.g., tunneling nanotubes, multiple kinds of extracellular vesicles, or several (inflammatory) mediators like cytokines and chemokines [ 10 , 11 , 12 ].…”