The Subventricular Zone in Glioblastoma: Genesis, Maintenance, and Modeling

Abstract

Glioblastoma (GBM) is a malignant tumor with a median survival rate of 15-16 months with standard care; however, cases of successful treatment offer hope that an enhanced understanding of the pathology will improve the prognosis. The cell of origin in GBM remains controversial. Recent evidence has implicated stem cells as cells of origin in many cancers. Neural stem/precursor cells (NSCs) are being evaluated as potential initiators of GBM tumorigenesis. The NSCs in the subventricular zone (SVZ) have demonstrated similar molecular profiles and share several distinctive characteristics to proliferative glioblastoma stem cells (GSCs) in GBM. Genomic and proteomic studies comparing the SVZ and GBM support the hypothesis that the tumor cells and SVZ cells are related. Animal models corroborate this connection, demonstrating migratory patterns from the SVZ to the tumor. Along with laboratory and animal research, clinical studies have demonstrated improved progression-free survival in patients with GBM after radiation to the ipsilateral SVZ. Additionally, key genetic mutations in GBM for the most part carry regulatory roles in the SVZ as well. An exciting avenue towards SVZ modeling and determining its role in gliomagenesis in the human context is human brain organoids. Here we comprehensively discuss and review the role of the SVZ in GBM genesis, maintenance, and modeling.

Opinion: Bridging gaps and doubts in glioblastoma cell-of-origin

“…A definitive cell of origin for GBM has still not been identified. The presence of a large, proliferative niche of NSCs in the SVZ of the adult brain, as well as the accumulating evidence of a stable, cycling NSC population in GBM models, continues to support NSCs as the most likely cell or origin (7,24,28,34,38). However, multi-omics analyses of genetically engineered models and patient samples suggest that differences in GBM-subtypes may be correlated to transcriptionally active oncogenic pathways that are cell of origin dependent, suggesting that multiple cells of origin may be responsible for the inter-tumoral heterogeneity seen in GBM (16,19,32).…”

“…Astrocytic-like NSCs give rise to transitamplifying cells (TACs), which in turn produce neuroblasts that migrate throughout the SVZ and along the rostral migratory stream (RMS) to the olfactory bulb where they can differentiate into immature neurons (36). Many molecular characteristics are shared between glioblastoma stem cells (GSCs) and NSCs, making the SVZ the main suspect of GBM tumorigenesis and recurrence (7,37).…”

“…Extensive cellular heterogeneity within these neoplasms results from malignant cells in multiple cellular states that dynamically react to their microenvironment (3)(4)(5)(6). The described heterogeneity within and between these tumors is believed to dictate the high treatment resistance and fatality rates of these central nervous system (CNS) malignancies (7)(8)(9). Drug screening has revealed significant differences in the response of genetically heterogeneous GSC cultures to cancer therapeutics, marking a significant barrier for establishing a standard of care that universally improves clinical outcomes (10,11).…”

Exosomes to control glioblastoma multiforme: Investigating the effects of mesenchymal stem cell‐derived exosomes on C6 cells in vitro

“…GBMs originate from transformed subventricular zone (SVZ) neural cells (Beiriger et al, 2022;G.-L. Zhang et al, 2021), or may arise from non-SVZ precursors or mature glial cells, which have undergone dedifferentiation. It is thought by them that genetic mutations of tumor preventers can be the major cause of this illness (Altaner, 2008).…”

“…Additionally, the inability to determine the origin of cancer cells has always been the main hindrance to further understanding of the nature of GBM, and the development of alternative treatments. Although their origination is not precisely known, researchers have made an assumption that GBMs originate from transformed subventricular zone (SVZ) neural cells (Beiriger et al, 2022; G.‐L. Zhang et al, 2021), or may arise from non‐SVZ precursors or mature glial cells, which have undergone dedifferentiation.…”