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Review
. 2020 Nov 27:10:602217.
doi: 10.3389/fonc.2020.602217. eCollection 2020.

To Become or Not to Become Tumorigenic: Subventricular Zone Versus Hippocampal Neural Stem Cells

Ángela Fontán-Lozano  1 , Sara Morcuende  1 , Mª América Davis-López de Carrizosa  1 , Beatriz Benítez-Temiño  1 , Rebeca Mejías  1 , Esperanza R Matarredona  1
Affiliations
Review

To Become or Not to Become Tumorigenic: Subventricular Zone Versus Hippocampal Neural Stem Cells

Ángela Fontán-Lozano et al. Front Oncol. .

Abstract

Neural stem cells (NSCs) persist in the adult mammalian brain in two neurogenic regions: the subventricular zone lining the lateral ventricles and the dentate gyrus of the hippocampus. Compelling evidence suggests that NSCs of the subventricular zone could be the cell type of origin of glioblastoma, the most devastating brain tumor. Studies in glioblastoma patients revealed that NSCs of the tumor-free subventricular zone, harbor cancer-driver mutations that were found in the tumor cells but were not present in normal cortical tissue. Endogenous mutagenesis can also take place in hippocampal NSCs. However, to date, no conclusive studies have linked hippocampal mutations with glioblastoma development. In addition, glioblastoma cells often invade or are closely located to the subventricular zone, whereas they do not tend to infiltrate into the hippocampus. In this review we will analyze possible causes by which subventricular zone NSCs might be more susceptible to malignant transformation than their hippocampal counterparts. Cellular and molecular differences between the two neurogenic niches, as well as genotypic and phenotypic characteristics of their respective NSCs will be discussed regarding why the cell type originating glioblastoma brain tumors has been linked mainly to subventricular zone, but not to hippocampal NSCs.

Keywords: cancer-driver mutations; glioblastoma; neural stem cells; neurogenesis; oncogenicity.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic drawings of the adult rodent subventricular zone (A) and hippocampus (B). Equivalent cell types within each niche are represented in the same color. (A). Ependymal cells (type E, in yellow) separate the cerebrospinal fluid (CSF) in the lateral ventricle from the brain parenchyma. Type B1 cells (in dark blue) are neural stem cells with a basal process in contact with blood vessels (BV) and an apical process in contact with the CSF. B1 cells generate type C cells (in green) by asymmetric divisions. Type C cells are transit-amplifying intermediate progenitors that divide rapidly and produce neuroblasts (type A, in orange). Neuroblasts migrate in chains ensheathed by astrocytes toward the olfactory bulb, where they differentiate into mature interneurons. Type C cells can also produce oligodendrocyte progenitor cells (O, in purple). Other glial cells, such as astrocytes (type B2, in sky blue), and microglia (in gray) intervene in the control of subventricular zone neurogenesis. (B). Neural stem cells (type 1, dark blue), located in the subgranular zone (SGZ) of the dentate gyrus of the hippocampus, harbor a basal process that contact BVs and numerous branches in the inner molecular layer (IML). Type 1 cells generate transit-amplifying non-radial type 2 cells (in green), which can be subdivided in type 2a and type 2b cells. Type 2 cells then give rise to a neuron-committed intermediate progenitor (type 3 cell, in orange). Type 3 cells generate fully functional granule cells in the granule cell layer (GCL) which, after maturation, develop dendritic arborization in the IML and axonal projection to the CA3. Microglia (gray) and astrocytes (sky blue) exert different roles in the control of neurogenesis.
Figure 2
Figure 2
Schematic drawing of the adult human subventricular zone (A) and hippocampus (B). (A) Astrocyte-like neural stem cells (NSCs, in dark blue) are located beneath the ependymal cell layer (in yellow) lining the lateral ventricles, within a hypocellular layer devoid of neuroblasts and transit-amplifying progenitor cells. Microglial cells in this layer are represented in gray. Putative oligodendrocyte progenitor cells generated from NSCs are shown in purple. NSCs contact the cerebrospinal fluid of the lateral ventricle and blood vessels (BV) of an adjacent layer consisted of a dense ribbon of astrocytes (pale blue) with processes in the hypocellular layer. (B) According to some studies (45, 46) the subgranular zone of the dentate gyrus of the adult human hippocampus contains radial glia-like neural stem cells (in pale blue) that generate proliferating intermediate neural progenitors (in pale green). These intermediate progenitors form neuronal committed progenitors (in pale orange) that become mature granule neurons (in orange). In contrast, other studies (47, 48) have reported the total absence of neuronal progenitors and immature neurons in the adult human subgranular zone. A question mark has been texted on these cells to symbolize this controversy. Other cell types of the niche are microglia (in gray) and astrocytes (in sky blue). GCL, granule cell layer; IML, inner molecular layer; SGZ, subgranular zone.
Figure 3
Figure 3
Schematic drawing summarizing different theories on the cell of origin of glioblastomas. Neural stem cells (NSC) of the subventricular zone, astrocytes and oligodendrocyte precursor cells (OPCs) of the brain parenchyma might acquire cancer-driver mutations leading to gliomas. Additionally, NSC-derived mutations can be transmitted to their progeny generating mutated neuroblasts and mutated astrocytes, that do not likely give rise to tumor formation, or mutated OPCs with the ability to grow aberrantly.
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