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.
Highlights
Glioblastoma (GBM) is the most common and most aggressive malignant glial tumor found in adults [1, 2]
While prognosis varies with factors such as age and specific mutations [2–4], GBM remains an incurable tumor with a median survival of 9 months without treatment and 15-16 months with treatment [5–7]
Earlier reports of lineage tracing methods [159] revealed significant aberrant growth prior to malignancy in oligodendrocyte precursor cells (OPCs). These findings suggest OPCs could be the major source of malignancy though initial mutations could occur in Neural stem/precursor cells (NSCs)
Summary
Glioblastoma (GBM) is the most common and most aggressive malignant glial tumor found in adults [1, 2]. The astrocyte dedifferentiation theory relies on the multi-step process of tumorigenesis leading a mature astrocyte to dedifferentiate to become a malignant stem-like cell This model is supported by recent experiments demonstrating the formation of tumors that are histologically similar to GBM after activation of oncogenes and suppression of tumor suppressor genes in astrocytes [47]. NSCs are self-renewing, multipotent cells in the brain responsible for differentiating into neurons, astrocytes, and oligodendrocytes [50–52] These cells are most active during development; recent evidence has suggested small populations in specific stem-cell niches remain functional in the adult brain [53–57]. The presence of cells with stem celllike characteristics has been identified in many cancers [60], including brain tumors [41, 44, 61] Clinical evidence supporting this theory includes the formation of a donorderived brain tumor after NSCs were injected intracerebrally and intrathecally into an Ataxia Telangiectasia patient [24]. Considering the heterogeneity of GBM, each of these theories may contribute a portion of the total tumor population included in the category of GBM
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