The Strange Case of Jekyll and Hyde: Parallels Between Neural Stem Cells and Glioblastoma-Initiating Cells

Abstract

During embryonic development, radial glial precursor cells give rise to neural lineages, and a small proportion persist in the adult mammalian brain to contribute to long-term neuroplasticity. Neural stem cells (NSCs) reside in two neurogenic niches of the adult brain, the hippocampus and the subventricular zone (SVZ). NSCs in the SVZ are endowed with the defining stem cell properties of self-renewal and multipotent differentiation, which are maintained by intrinsic cellular programs, and extrinsic cellular and niche-specific interactions. In glioblastoma, the most aggressive primary malignant brain cancer, a subpopulation of cells termed glioblastoma stem cells (GSCs) exhibit similar stem-like properties. While there is an extensive overlap between NSCs and GSCs in function, distinct genetic profiles, transcriptional programs, and external environmental cues influence their divergent behavior. This review highlights the similarities and differences between GSCs and SVZ NSCs in terms of their gene expression, regulatory molecular pathways, niche organization, metabolic programs, and current therapies designed to exploit these differences.

Keywords: glioblastoma stem cells; neural stem cells; neurogenic niche; tumor metabolism; tumor microenvironment.

Figure 1

Differences in cytoarchitectures surrounding subventricular zone (SVZ) neural stem cells (NSCs) and glioblastoma stem cells (GSCs). (A) A schematic representation of adult human SVZ. Human SVZ is composed of four distinct layers. The superficial ependymal monolayer, Lamina I, is in contact with ventricular lumen. The second layer, Lamina II is a vastly acellular layer formed by the neuroblast depletion, containing ependymal expansions and numerous astrocyte processes. Lamina III, is a region known as astrocytic ribbon, containing densely packed astrocytes. Lastly, Lamina IV is a transitional zone rich in oligodendrocytes and myelinated neurons. The NSC niche is an extensive microenvironment that hosts cell-cell and cell-microenvironment interactions that contribute extensively to the extrinsic regulation of NSC proliferation and self-renewal. (B) A schematic representation of three major microenvironments within glioblastoma (GBM) tumors. The hypoxia region formed in the course of tumor growth lacks any blood and oxygen supply and has been implicated in playing a protective role against chemoradiotherapy. Perivascular niches exist along capillaries or arterioles where endothelial cells come into direct contact with glioblastoma cells. In addition to producing high levels of pro-angiogenic factors driving tumor vascularization, cells in the perivascular contribute to activation of pathways regulating self-renewal and proliferation of GSCs. As a highly invasive tumor, GBMs can infiltrate into healthy brain tissue and limit the effectiveness of surgical interventions.

Figure 2

Schematic representation of key genetic and signaling difference between subventricular zone (SVZ) neural stem cells (NSCs) and glioblastoma stem cells (GSCs).