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Neural Stem Cells as Potential Glioblastoma Cells of Origin

Alba Loras
Luis G. Gonzalez-Bonet
Julia L. Gutierrez-Arroyo
Conrado Martinez-Cadenas
2 and
Maria Angeles Marques-Torrejon
Department of Medicine, University of Valencia, 46010 Valencia, Spain
Department of Medicine, Jaume I University of Castellon, 12071 Castellon de la Plana, Spain
Department of Neurosurgery, Castellon General University Hospital, 12004 Castellon de la Plana, Spain
Author to whom correspondence should be addressed.
Life 2023, 13(4), 905;
Submission received: 17 January 2023 / Revised: 24 March 2023 / Accepted: 27 March 2023 / Published: 29 March 2023
(This article belongs to the Section Physiology and Pathology)


Glioblastoma multiforme (GBM) is the most malignant brain tumor in adults and it remains incurable. These tumors are very heterogeneous, resistant to cytotoxic therapies, and they show high rates of invasiveness. Therefore, patients face poor prognosis, and the survival rates remain very low. Previous research states that GBM contains a cell population with stem cell characteristics called glioma stem cells (GSCs). These cells are able to self-renew and regenerate the tumor and, therefore, they are partly responsible for the observed resistance to therapies and tumor recurrence. Recent data indicate that neural stem cells (NSCs) in the subventricular zone (SVZ) are the cells of origin of GBM, that is, the cell type acquiring the initial tumorigenic mutation. The involvement of SVZ-NSCs is also associated with GBM progression and recurrence. Identifying the cellular origin of GBM is important for the development of early detection techniques and the discovery of early disease markers. In this review, we analyze the SVZ-NSC population as a potential GBM cell of origin, and its potential role for GBM therapies.

1. Introduction

1.1. Glioblastoma

Glioblastoma multiforme (GBM) is the most complex, aggressive, and deadly human brain tumor. The World Health Organization classifies GBM as a Grade IV tumor [1]. Today, despite surgery, chemotherapy, and radiotherapy treatments, the survival rate for these tumors is very low and it oscillates around 16 months [2,3]. There are no treatments that have significantly prolonged survival, with 5-year survival rates of about 6% [4]. Much of the failure of conventional therapies is due to the existence of inter- and intra- tumor heterogeneity [5,6,7].
Based on the cancer genome atlas (TCGA), GBM has been classified into four subtypes: proneural, neural, classical, and mesenchymal, with the mesenchymal subtype being the most aggressive subtype with the worst prognosis [6,8,9,10]. Later studies propose a different classification system based on IDH (Isocitrate dehydrogenase) gene mutation status: tumors classified as IDH wild-type, IDH mutant, and patients whose full IDH analysis cannot be determined called GBM NOS (not otherwise specified) [1]. Another reason for intra-tumoral heterogeneity is the presence of cells with stem-like features, called glioma stem cells (GSCs). These cells can self-renew, differentiate into different lineages, show high resistance to cytotoxic and radio- therapies, and display high tumorigenicity [9,11,12,13].
Age-adjusted annual incidence values of GBM fluctuate between 0.6 and 3.7 per 100,000 people [14]. In general, GBM is diagnosed in elderly patients, with a median age of about 64 years. Incidence rates increase with age, peaking between 75 and 84 years [15]. Primary GBM is usually diagnosed between 55 and 64 years of age, while secondary GBM is diagnosed around 40 years of age [16]. However, GBM is extremely rare in children [15].
The most evident sex-related difference in GBM is the prevalence rates. Malignant brain tumors are more frequent in males than females, with GBM rates 1.6 times higher in men than in women. However, there is no difference in the incidence of low-grade gliomas. Regarding GBM subtypes, primary tumors are more frequent in males, but secondary tumors appear more frequently in females. Both in human and animal research, higher survival is found in females [4,17,18,19,20,21]. Unfortunately, tumor recurrence is unavoidable and appears in a short time period, irrespective of gender.
Most GBMs occur as primary tumors (90%), without the existence of a previous tumor, and are frequent in elderly patients. On the other hand, in younger patients, GBMs usually appear following a low-grade lesion, and therefore, they occur as secondary tumors. Both tumors do not differ histologically, but secondary tumors are genetically characterized by the presence of a mutation in the IDH1 gene. Primary and secondary GBMs are therefore called the IDH1 wild-type and IDH1 mutant, respectively [1,22]. Both GBM subtypes usually present mutations in the deregulation of different pathways, such as the tumor-suppressor p53 signaling pathway (CDKN2A, MDM2, TP53 genes), NF1 (neurofibromin 1) gene mutations, or TERT (telomerase reverse transcriptase) gene mutations [10,23,24]. Likewise, primary GBMs are characterized by EGFR overexpression, PTEN mutations, and CDKN2A (p16) deletions, while the most common and detectable alteration in secondary GBM, other than IDH1 gene mutations, is the presence of TP53 gene mutations [6].
Six subgroups of DNA methylation, DNA copy number alterations, and transcriptomic patterns have been found in adult and pediatric GBMs. Two of these subgroups have been found to affect essential amino acids (K27 and G34) in histone H3.3 and are predominantly found in children and adolescent patients [25].

1.2. The Potential GBM Cell of Origin

The cellular origin of GBM refers to the ordinary cell that is susceptible to oncogenic mutations and therefore, has the physiological potential to transform into a cancerous cell and generate a tumor. Identifying the cellular origin may therefore lead to the development of more effective and perhaps preventive therapies. The definition of the cell of origin, as the cell type initiating a glioma, is therefore different from that of the glioma stem cell (GSC), since the latter concept refers to a cellular subtype existing in the tumor that is acting as a reservoir for tumor regeneration.
To determine the cellular origin of gliomas, it is essential to understand the development of glial cells in mammals [26]. During the development of the central nervous system (CNS), NSCs reside in the ventricles of the brain. However, in the adult brain, they will only remain in two specific regions, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus [27,28]. These NSCs will generate glial cells (astrocytes and oligodendrocytes) and neurons [27,29,30,31]. At the end of embryonic development, most progenitor cells undergo terminal differentiation, with the exception of oligodendrocyte precursor cells (OPCs). These OPCs remain undifferentiated and can proliferate in the adult brain [32,33]. In addition to NSCs and OPCs, astrocytes, which are differentiated cells, retain some proliferative capacity, particularly after brain injury [34]. Because NSCs, OPCs, and astrocytes all have some regenerative potential, they all present a potential source of cells for initiating gliomas [35,36] (Figure 1).
In order to become tumorigenic, astrocytes require a multistep process. Firstly, they must dedifferentiate and, secondly, they need to acquire tumor characteristics, including oncogene and tumor-suppressor modifications. In comparison, NSCs and OPCs are already proliferative and therefore only require oncogene and/or tumor-suppressor alterations. Thus, they present a more feasible GBM cell of origin. A recent publication shows that astrocyte precursors and OPCs can generate brain tumors involving driver mutations in NSCs that promote carcinogenesis after committing to the oligodendrocyte line [37]. Clinically, it has been shown in humans that NSCs, after transplantation as potential therapies for neurodegenerative diseases, can participate in the process of brain tumor formation [38].

1.3. The Human SVZ

The SVZ is one of the adult mammalian neurogenesis niches [39,40,41]. It is well known that NSCs have astrocytic features and self-renewal and multipotency capacities (differentiation into neurons, oligodendrocytes, and astrocytes) [27,39,42]. The SVZ area lines the lateral ventricles of the brain, and it is composed of different types of cells in a well-organized pattern (Figure 2) [43]. Although neurogenesis in this area persists throughout life, from fetal to adult stages, this neurogenic capacity undergoes a significant decrease with age [41,44]. Compared to the rodent SVZ, the human SVZ is organized differently. It is divided into four layers: (i) the ependymal layer, which lines the lateral ventricle where CSF (cerebrospinal fluid) flows and is composed of multi-ciliated ependymal cells; (ii) the hypocellular layer, which contains extensions of astrocytes; (iii) a layer containing three distinct types of astrocytes; and finally, (iv) a layer with myelinated axons and oligodendrocytes [41]. In the human SVZ, in contrast to the rodent SVZ, there is no evidence of fast proliferating precursor cells, and neither the existence of a rostral migratory stream (RMS) with neuroblasts migrating to the olfactory bulb (OB) [39,45,46]. In the pediatric human SVZ, NSCs generate neurons that migrate both to the prefrontal cortex and to the forebrain [47,48]. In contrast, neurogenesis is a rare event in the adult human SVZ, although there is restricted neurogenesis in the nearby striatum [39,49].

1.4. Similarities between NSCs and Glioma Stem Cells

Many characteristics are shared between NSCs and GSCs, as seen by genome-wide CRISPR-Cas9 screens [50]. SOX2 is one of the most important players for the maintenance of both NSCs and GSCs, and SOCS3, a protein responsible for maintaining stemness in NSCs, is also an important GBM-specific fitness gene in GSCs [50]. There is also evidence for developmental patterns being activated in GBM. For example, some genes such as CDK6, SQLE, and DOTIL have great scores with NSCs. However, JUN and SOX9 display lower scores [50]. These findings indicate that gene networks shared with NSCs are important for GSC maintenance, while GBM-specific genes promote the generation of tumorigenic GSCs [50].
Proteomic analyses have also revealed similarities between NSCs and GSCs [51,52,53,54,55,56,57,58]. Multiple signaling pathways that are necessary for self-renewal have been shown to be active in both NSCs and GSCs, and vimentin is overexpressed in both cell types [52,53,54,55,56,57,58,59]. It is known that the Notch pathway is required to maintain the undifferentiated state of NSCs by inhibiting proneural gene expression. This pathway has been found to be upregulated in GSCs [60,61]. The BMP pathway promotes gliogenesis and inhibits neurogenesis in NSCs [62,63]. BMP has been shown to promote astrocyte differentiation and decrease proliferation in NSCs and GSCs [64,65,66,67]. The Wnt and β-catenin signaling pathways control both NSC and GSC proliferation [68,69]. In addition, the sonic hedgehog pathway regulates the self-renewal of both NSCs and GSCs through Gli1 [56,70]. STAT3 is necessary for proliferation and multipotency regulation in NSCs and GSCs [71,72]. Some growth factors that are required during development are also secreted by GSCs, such as the endothelial growth factor (VEGF), the basic fibroblast growth factor (bFGF), the transforming growth factor alpha (TGF-alpha), and the stromal-derived factor (SDF1) [73,74,75,76,77,78]. One study examined 19 chromosome proteins in GSCs and encountered the upregulation of many molecular pathways associated with development [79]. Together, these molecular similarities between NSCs and GSCs, involving stemness and development signatures, indicate NSCs as the potential GBM cell of origin.

1.5. NSCs of the SVZ as the GBM Cell of Origin

Evidence suggests that GSCs could originate from SVZ-NSCs, as these cells are more susceptible to oncogenic transformation than SGZ-NSCs of the hippocampus or differentiated cells [80]. Furthermore, human SVZ-NSCs are more susceptible to malignant transformation as they mainly generate OPCs [81]. The SVZ is chemo-attractive for glioma cells, and microglia are supportive cells for neurogenesis [82]. SVZ-NSCs line the lateral ventricles and are in contact with the CSF, which are rich in factors that could promote and maintain the tumor [83,84]. SVZ-NSCs do not display an expression of HOPX, a tumor-suppressor gene, and mutations in the TERT gene promoter could activate senescence [80,85].
The regenerative plasticity and the developmental potential of NSCs, with their intrinsic properties—self-renewal, proliferation, apoptosis, and senescence avoidance—make them a suitable potential glioma cell of origin [86]. Clinically, both a complex cellular composition and the existence of multilineage markers within the tumor have been observed, suggesting ongoing differentiation. However, there may also be dedifferentiation of the committed cell progenitors. Cultured cancer cells tend to exhibit numerous NSC markers, develop renewable tumor spheres, and differentiate into numerous cell types upon serum stimulation, all of which, are NSC features [87].
Although these data are promising, it remains difficult to definitively identify the GBM cell of origin using endpoint studies. Confirmation must come from studies of genetically modified animal models, in which physiologically significant tumor-driver mutations allow for the analysis of early events in tumor formation [88,89].
In order to precisely identify the cellular origin of the tumor in vivo, it is critical to use specific methods to produce mutations only in selected cells. For example, retrovirus vectors are widely used to induce mutations in a small number of cells or in restricted areas of the brain [90]. This makes it possible to discern between tumors arising from resident cells versus cells that break away from the tumor mass to colonize distant areas. With the retroviral approach and using different combinations of PTEN, TP53, NF1, and RB1 mutations, NSCs have been identified as a possible cellular origin of GBM in mouse models [91,92,93]. In addition, tumor formation was found to be dependent on the niche in which the cells were located. This type of study tests the ability of tumors to originate in specific regions of the brain and also shows that SVZ-NSCs are more readily converted into cancerous cells than differentiated cells outside this region [93]. These studies show the tendency of NSCs to serve as the GBM cell of origin; however, they do not discount the fact that alternative cell types, especially progenitor cells, could also be putative cells of origin for GBM.
Recently, research has shown the first genetic confirmation of the cell of origin in human GBM [37]. This study shows that in 56.3% of cases of IDH1 wild-type GBM, the SVZ tissue contained driver mutations in genes such as TP53, PTEN, and EGFR [37]. Additionally, 42.3% of patients had TERT-promoter mutations in the SVZ tissue as well as in the tumor tissue [37]. Furthermore, they also demonstrated that SVZ-NSCs harboring oncogenic mutations were able to travel and form GBMs in remote brain areas [37]. These findings reveal that human SVZ cells can harbor cancer driver mutations, at least in IDH1 wild-type GBMs. Remarkably, TERT-promoter mutations in the SVZ area were found in all patients with IDH1 wild-type tumors. SVZ-NSCs exhibit only a partial self-renewal capacity and therefore, they could avoid telomere shortening and increase the possibility of acquiring driver mutations [37]. However, this study did not find evidence of the cell of origin in IDH1-mutant GBMs. Moreover, in 7 out of the 16 GBM samples, they did not find mutations in the SVZ, which suggests that SVZ-NSCs may not be the cell of origin for all IDH1 wild-type GBMs [37]. The concept of dedifferentiation as an alternative for the cell of origin has been established using mouse experimentation, and no confirmation in humans has been shown in this study. They also generated a murine model of PT53, EGFR, and PTEN mutations through genome editing, with the same mutations that were present in the SVZ of GBM patients [37]. Subsequently, 90% of the animals with these mutations ended up developing brain tumors, and 67% of these tumors were found in distant areas from the SVZ [37]. In addition, SVZ NSCs carrying these mutations were able to migrate a great distance to the olfactory bulb (OB) and differentiate into neurons, without the generation of tumors [37]. It is therefore vital to understand the niche signaling in different areas of the brain, since this could promote tumor generation or differentiation. Understanding niche signaling will be of critical importance in the design of new therapies for this disease.

2. Materials and Methods

An exhaustive bibliographic search of English-language publications available in PubMed and Scopus databases was performed. No limits were used on the publication dates of the articles. The keywords used for the bibliographic search in this article were as follows: GBM, cell of origin, and NSCs. In addition, the reference lists of relevant articles and published reviews were revised in order to identify additional studies. Publications in a language other than English were excluded. No studies were excluded a priori due to poor design or data quality. Articles were first selected by titles and abstracts. If the information in the abstract was not detailed, the full text was reviewed.

3. Discussion

Recent evidence indicates that the heterogeneity of GBM could be linked to its cell of origin and have stem cell properties [13,94]. For a long time, neuroscientists have focused their attention on the SVZ as the potential brain area of GBM origin (or at least contributor). Scientific evidence shows that more than 50% of the GBMs are located near the SVZ, and that this location is associated with poor prognosis [95,96]. NSCs are close to the lateral ventricles and the recruitment of these cells to the tumor could enhance GBM aggressiveness. It has also been shown that the relationship between GBM and the SVZ is associated with multifocality and recurrence [82,97]. In addition, some studies in humans suggest that the enhanced radiotherapy of the SVZ is associated with a longer survival of GBM patients [2,3].
However, there are still many human brain tumors situated in distant areas other than the SVZ [98]. This could be explained by the asymmetric division of NSCs into two daughter cells with different proliferative and migrative features [98,99]. One of these daughter cells could stay in the SVZ, while the other could migrate a great distance to form the tumor mass in a different brain area [100]. These migrating tumor cells are possibly GSCs that have previously been transformed within the SVZ [100]. In fact, a similar event occurs during brain development, where radial glial cells migrate to the cortex and then differentiate [26]. The fact that gliomas usually recur nearby could also be explained, since secondary tumors derive from primary tumors and do not form in the SVZ. Classical therapies (surgery, radiation, and chemotherapies) remove the bulk of the tumor mass, but it is thought that some cells are able to survive; these cells could be the source of the cells that are responsible, in a short period of time, for the formation of secondary tumors that are close to the primary site [1].
There is evidence that secondary GBMs (IDH1-mutant) could have different potential cellular origins to primary GBMs (IDH1 wild-type) [101]. Accordingly, different genetic and animal approaches should be considered in order to understand the mechanisms through which cells acquire mutations and undergo lineage specification during gliomagenesis [102]. In this context, it would be interesting to study how the niche influences GSCs fate and its impact on the development of the different subtypes of GBM.
Another fascinating prospect is that secondary GBMs are derived from the SVZ, where a primary GBM may “replenish” NSCs from the SVZ [103]. This circumstance of attracting regular cells to become part of the tumor mass has been observed through the production and release of trophic molecules into the tumor niche [104]. This may also be contributing to tumor heterogeneity [105,106]. Additionally, in rodent models, it has been shown that NSCs are highly trophic and migrate to the tumor following these signals [105,107,108]. These findings could be important to understand tumor resistance to current therapies, as tumor-free areas may be occupied by migrating cells [98].
Nevertheless, there is evidence that associates GBM with the SVZ. A complex in vitro 3D model or organoid system similar to the SVZ and its niche would be necessary to accurately study this association. Using this model, the structure and cytoarchitecture of the SVZ would be recreated exactly, and different regions of the brain could be studied as potential areas involved in tumor formation. Such studies could greatly enhance the possibilities of finding new potential therapeutic targets.
Although this review has focused on SVZ NSCs as the best candidate for the GBM cell of origin, all three candidate cell types (NSCs, astrocytes, and OPCs) have established regeneration potential in the brain. This implies that the tumorigenic transformation of these cells is determined by their oncogenic mutations and their regeneration capacities. GBM is a very diverse disease and it presents a great diversity of clinical and histopathological characteristics. This could be due to GBMs being intrinsically derived from different cell types.
Clinical data from GBMs may suggest evidence for putative cellular origins; however, drawing conclusions from clinical data has proven complex, as human tumors are usually studied at the terminal stage [82]. An important issue to consider is that the different subtypes of GBM defined by TCGA data could be due to different cellular origins [82]. In fact, gene expression profiles of the proneural GBM subtype are compatible with that of OPCs, and the profiles of other GBM subtypes correspond to those of NSCs or astrocytes. In addition, different developmental potential cells of origin have also been suggested [109] to explain the different potential GBM cell of origin; multiple cell types could function as the developmental origins of different GBM subtypes. For this it would be necessary to dissect each transforming process and analyze them temporally and spatially, frame by frame, in order to obtain the applicable information for therapeutic purposes.
The use of markers to track tumor cells of origin can be difficult, as studies are performed at the later stages of tumor evolution. It is therefore important to carry out studies of cell type-specific gene expression profiles using transcriptomic analysis instead of candidate gene analyses [6,110]. In this way, genomics may produce significant advances in the knowledge of novel molecular mechanisms involved in gliomas.
Murine genetic models are extremely useful in allowing us to trace the cellular origin of GBM from its initial stages. In this way, it is possible to obtain a temporal and spatial analysis of tumor formation. In addition, these animal models may be used in preclinical trials of potential drugs. However, the differences between human and mouse cell populations must be considered, and the upcoming results must therefore be carefully translated to human cells and tissue before clinical translational approaches.
The study of the different cell states of NSCs (proliferation, quiescence, and differentiation) also aids our understanding of the possible cell states of the GBM population and potential therapies. Focus is needed on eliminating the proliferating tumor population through antiproliferative therapies such as temozolomide (TMZ), radiotherapy, and EGFR inhibitors. Unfortunately, the potential for cellular reprogramming and dedifferentiation within the tumor makes conventional therapies ineffective. Targeting specific tumor characteristics such as proliferation (chemotherapy, radiotherapy, and EGFR inhibitors) and network integration (e.g., ion channel modulators) can eliminate specific tumor populations and may induce differentiation to improve GBM treatment efficiency. For example, it is known that the disruption of OLIG2 induces cell differentiation [111]. Similarly, the removal of growth factors and the addition of bone morphogenic protein (BMP4) induces the cell cycle exit and differentiation of GSCs [112]. However, this cell differentiation depends on the disruption of the signaling pathway between the transcription factor and the receptor tyrosine kinase’s signaling. Moreover, even if there were targeted therapies for differentiated cells, not all cells differentiate. It has been shown that differentiation is induced by reversible histone modifications of CpG islands [112]. Consequently, as these histone modifications are reversible, cells re-enter the cell cycle. Therefore, cell differentiation as an antitumor therapy must be terminal. Neurogenic differentiation and reduced tumor formation have been shown to be diminished by Notch signaling or MASH1 inhibition in GBM [113]. The most effective antitumor therapy would therefore be one that completely differentiates tumor cells, whether proliferating, dormant, or any cell type, from neuronal differentiation, which is irreversible. The side effect of such therapies on the differentiated population such as neurons and glia would also have to be considered.
The fundamental aim in studying the cell of origin of GBM is to find new therapeutic targets for this disease [114]. Different origins may imply different prognoses and responsiveness to treatments. Understanding the cellular origin would therefore allow us to classify patients and develop more personalized and effective treatments. Drugs could be developed considering different parameters. Firstly, specific membrane proteins would allow for the use of selective drug administration, reducing the toxicity to other brain cells [115]. Secondly, the possibility of susceptibility to certain genetic mutations and therefore to the activation or inhibition of certain signaling pathways could be avoided [18]. It would be effective to target the interactions between signaling pathways and tumorigenic mutations. Finally, knowledge of the cell of origin would further the connection between oncology and the field of regenerative medicine. For example, the study of the enhanced self-renewal capacity in NSC and tumor progenitor cells could shed light on NSCs expansion in regenerative medicine. Similarly, understanding the differentiation process in NSCs and progenitors could be a challenge for GBM therapy; this strategy has great potential because it would reduce tumor progression while avoiding cytotoxic drug resistance.

4. Conclusions

In conclusion, studies on the GBM cell of origin have not yet reached a clear conclusion. In fact, it could almost be stated that these studies have just begun. The study of adult neurogenic niches is currently a very active research topic. In addition to their function as neural cell generators, new data have identified neurogenic niches as modulators of brain tumors (as they are partly responsible for both their origin and maintenance, as well as a source of recurrence). Due to its special characteristics, the SVZ seems to be the neurogenic niche that could be responsible for the generation of gliomas. There are different cell types in this region of the brain that could act as the potential cellular origin of GBM tumors.
In order to progress in both the understanding and treatment of this devasting disease, it is necessary to implement innovative technologies and assimilate new concepts into our current knowledge. While our knowledge progresses faster than those GSCs, effective treatment for GBM should be within our scope.

Author Contributions

Conceptualization, M.A.M.-T. and L.G.G.-B.; methodology, M.A.M.-T., A.L. and J.L.G.-A.; investigation, M.A.M.-T., J.L.G.-A., A.L. and C.M.-C.; writing—original draft preparation, M.A.M.-T., A.L., L.G.G.-B. and C.M.-C.; writing—review and editing, M.A.M.-T. and C.M.-C.; supervision, M.A.M.-T. and L.G.G.-B. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.


AL acknowledges a “Margarita Salas” postdoctoral contract (number 21-076), and MAM-T a ‘Maria Zambrano’ research contract (number MAZ/2021/03 UP2021-021). Both contracts have been funded by the European Union-Next generation EU. We thank Kirsty M. Ferguson for reading the manuscript and for her suggestions.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Louis, D.N.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, W.K.; Ohgaki, H.; Wiestler, O.D.; Kleihues, P.; Ellison, D.W. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A Summary. Acta Neuropathol. 2016, 131, 803–820. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Stupp, R.; Mason, W.P.; van den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.B.; Belanger, K.; Brandes, A.A.; Marosi, C.; Bogdahn, U.; et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N. Engl. J. Med. 2005, 352, 987–996. [Google Scholar] [CrossRef] [Green Version]
  3. Stupp, R.; Hegi, M.E.; Mason, W.P.; van den Bent, M.J.; Taphoorn, M.J.; Janzer, R.C.; Ludwin, S.K.; Allgeier, A.; Fisher, B.; Belanger, K.; et al. Effects of Radiotherapy with Concomitant and Adjuvant Temozolomide versus Radiotherapy Alone on Survival in Glioblastoma in a Randomised Phase III Study: 5-Year Analysis of the EORTC-NCIC Trial. Lancet Oncol. 2009, 10, 459–466. [Google Scholar] [CrossRef] [PubMed]
  4. Thakkar, J.P.; Dolecek, T.A.; Horbinski, C.; Ostrom, Q.T.; Lightner, D.D.; Barnholtz-Sloan, J.S.; Villano, J.L. Epidemiologic and Molecular Prognostic Review of Glioblastoma. Cancer Epidemiol. Biomark. Prev. 2014, 23, 1985–1996. [Google Scholar] [CrossRef] [Green Version]
  5. Neftel, C.; Laffy, J.; Filbin, M.G.; Hara, T.; Shore, M.E.; Rahme, G.J.; Richman, A.R.; Silverbush, D.; Shaw, M.L.; Hebert, C.M.; et al. An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma. Cell 2019, 178, 835–849.e21. [Google Scholar] [CrossRef] [PubMed]
  6. Verhaak, R.G.W.; Hoadley, K.A.; Purdom, E.; Wang, V.; Qi, Y.; Wilkerson, M.D.; Miller, C.R.; Ding, L.; Golub, T.; Mesirov, J.P.; et al. Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010, 17, 98–110. [Google Scholar] [CrossRef] [Green Version]
  7. Patel, A.P.; Tirosh, I.; Trombetta, J.J.; Shalek, A.K.; Gillespie, S.M.; Wakimoto, H.; Cahill, D.P.; Nahed, B.V.; Curry, W.T.; Martuza, R.L.; et al. Single-Cell RNA-Seq Highlights Intratumoral Heterogeneity in Primary Glioblastoma. Science 2014, 344, 1396–1401. [Google Scholar] [CrossRef] [Green Version]
  8. Wang, Q.; Hu, B.; Hu, X.; Kim, H.; Squatrito, M.; Scarpace, L.; deCarvalho, A.C.; Lyu, S.; Li, P.; Li, Y.; et al. Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell 2017, 32, 42–56.e6. [Google Scholar] [CrossRef] [Green Version]
  9. Phillips, H.S.; Kharbanda, S.; Chen, R.; Forrest, W.F.; Soriano, R.H.; Wu, T.D.; Misra, A.; Nigro, J.M.; Colman, H.; Soroceanu, L.; et al. Molecular Subclasses of High-Grade Glioma Predict Prognosis, Delineate a Pattern of Disease Progression, and Resemble Stages in Neurogenesis. Cancer Cell 2006, 9, 157–173. [Google Scholar] [CrossRef] [Green Version]
  10. Brennan, C.W.; Verhaak, R.G.W.; McKenna, A.; Campos, B.; Noushmehr, H.; Salama, S.R.; Zheng, S.; Chakravarty, D.; Sanborn, J.Z.; Berman, S.H.; et al. The Somatic Genomic Landscape of Glioblastoma. Cell 2013, 155, 462–477. [Google Scholar] [CrossRef]
  11. Bao, S.; Wu, Q.; McLendon, R.E.; Hao, Y.; Shi, Q.; Hjelmeland, A.B.; Dewhirst, M.W.; Bigner, D.D.; Rich, J.N. Glioma Stem Cells Promote Radioresistance by Preferential Activation of the DNA Damage Response. Nature 2006, 444, 756–760. [Google Scholar] [CrossRef] [PubMed]
  12. Gimple, R.C.; Bhargava, S.; Dixit, D.; Rich, J.N. Glioblastoma Stem Cells: Lessons from the Tumor Hierarchy in a Lethal Cancer. Genes Dev. 2019, 33, 591–609. [Google Scholar] [CrossRef] [PubMed]
  13. Singh, S.K.; Clarke, I.D.; Terasaki, M.; Bonn, V.E.; Hawkins, C.; Squire, J.; Dirks, P.B. Identification of a Cancer Stem Cell in Human Brain Tumors. Cancer Res. 2003, 63, 5821–5828. [Google Scholar] [PubMed]
  14. Hauser, A.; Dutta, S.W.; Showalter, T.N.; Sheehan, J.P.; Grover, S.; Trifiletti, D.M. Impact of Academic Facility Type and Volume on Post-Surgical Outcomes Following Diagnosis of Glioblastoma. J. Clin. Neurosci. 2018, 47, 103–110. [Google Scholar] [CrossRef]
  15. Ostrom, Q.T.; Gittleman, H.; Farah, P.; Ondracek, A.; Chen, Y.; Wolinsky, Y.; Stroup, N.E.; Kruchko, C.; Barnholtz-Sloan, J.S. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2006–2010. Neuro-Oncology 2013, 15, ii1–ii56. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Wilson, T.; Karajannis, M.; Harter, D. Glioblastoma Multiforme: State of the Art and Future Therapeutics. Surg. Neurol. Int. 2014, 5, 64. [Google Scholar] [CrossRef]
  17. Cantrell, J.N.; Waddle, M.R.; Rotman, M.; Peterson, J.L.; Ruiz-Garcia, H.; Heckman, M.G.; Quiñones-Hinojosa, A.; Rosenfeld, S.S.; Brown, P.D.; Trifiletti, D.M. Progress Toward Long-Term Survivors of Glioblastoma. Mayo Clin. Proc. 2019, 94, 1278–1286. [Google Scholar] [CrossRef]
  18. Ohgaki, H.; Dessen, P.; Jourde, B.; Horstmann, S.; Nishikawa, T.; Di Patre, P.-L.; Burkhard, C.; Schüler, D.; Probst-Hensch, N.M.; Maiorka, P.C.; et al. Genetic Pathways to Glioblastoma. Cancer Res. 2004, 64, 6892–6899. [Google Scholar] [CrossRef] [Green Version]
  19. Pan, I.-W.; Ferguson, S.D.; Lam, S. Patient and Treatment Factors Associated with Survival among Adult Glioblastoma Patients: A USA Population-Based Study from 2000–2010. J. Clin. Neurosci. 2015, 22, 1575–1581. [Google Scholar] [CrossRef]
  20. Franceschi, E.; Tosoni, A.; Minichillo, S.; Depenni, R.; Paccapelo, A.; Bartolini, S.; Michiara, M.; Pavesi, G.; Urbini, B.; Crisi, G.; et al. The Prognostic Roles of Gender and O6-Methylguanine-DNA Methyltransferase Methylation Status in Glioblastoma Patients: The Female Power. World Neurosurg. 2018, 112, e342–e347. [Google Scholar] [CrossRef]
  21. McCrea, H.J.; Bander, E.D.; Venn, R.A.; Reiner, A.S.; Iorgulescu, J.B.; Puchi, L.A.; Schaefer, P.M.; Cederquist, G.; Greenfield, J.P. Sex, Age, Anatomic Location, and Extent of Resection Influence Outcomes in Children With High-Grade Glioma. Neurosurgery 2015, 77, 443–453. [Google Scholar] [CrossRef] [PubMed]
  22. Nobusawa, S.; Watanabe, T.; Kleihues, P.; Ohgaki, H. IDH1 Mutations as Molecular Signature and Predictive Factor of Secondary Glioblastomas. Clin. Cancer Res. 2009, 15, 6002–6007. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Zheng, H.; Ying, H.; Yan, H.; Kimmelman, A.C.; Hiller, D.J.; Chen, A.-J.; Perry, S.R.; Tonon, G.; Chu, G.C.; Ding, Z.; et al. P53 and Pten Control Neural and Glioma Stem/Progenitor Cell Renewal and Differentiation. Nature 2008, 455, 1129–1133. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Killela, P.J.; Reitman, Z.J.; Jiao, Y.; Bettegowda, C.; Agrawal, N.; Diaz, L.A.; Friedman, A.H.; Friedman, H.; Gallia, G.L.; Giovanella, B.C.; et al. TERT Promoter Mutations Occur Frequently in Gliomas and a Subset of Tumors Derived from Cells with Low Rates of Self-Renewal. Proc. Natl. Acad. Sci. USA 2013, 110, 6021–6026. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Sturm, D.; Bender, S.; Jones, D.T.W.; Lichter, P.; Grill, J.; Becher, O.; Hawkins, C.; Majewski, J.; Jones, C.; Costello, J.F.; et al. Paediatric and Adult Glioblastoma: Multiform (Epi)Genomic Culprits Emerge. Nat. Rev. Cancer 2014, 14, 92–107. [Google Scholar] [CrossRef] [Green Version]
  26. Götz, M.; Barde, Y.-A. Radial Glial Cells. Neuron 2005, 46, 369–372. [Google Scholar] [CrossRef] [Green Version]
  27. Doetsch, F.; Caillé, I.; Lim, D.A.; García-Verdugo, J.M.; Alvarez-Buylla, A. Subventricular Zone Astrocytes Are Neural Stem Cells in the Adult Mammalian Brain. Cell 1999, 97, 703–716. [Google Scholar] [CrossRef] [Green Version]
  28. Gage, F.H. Mammalian Neural Stem Cells. Science 2000, 287, 1433–1438. [Google Scholar] [CrossRef]
  29. Ge, W.-P.; Miyawaki, A.; Gage, F.H.; Jan, Y.N.; Jan, L.Y. Local Generation of Glia Is a Major Astrocyte Source in Postnatal Cortex. Nature 2012, 484, 376–380. [Google Scholar] [CrossRef] [Green Version]
  30. Gage, F.H.; Temple, S. Neural Stem Cells: Generating and Regenerating the Brain. Neuron 2013, 80, 588–601. [Google Scholar] [CrossRef] [Green Version]
  31. Rowitch, D.H. Glial Specification in the Vertebrate Neural Tube. Nat. Rev. Neurosci. 2004, 5, 409–419. [Google Scholar] [CrossRef]
  32. ffrench-Constant, C.; Raff, M.C. Proliferating Bipotential Glial Progenitor Cells in Adult Rat Optic Nerve. Nature 1986, 319, 499–502. [Google Scholar] [CrossRef] [PubMed]
  33. Imamoto, K.; Leblond, C.P. Radioautographic Investigation of Gliogenesis in the Corpus Callosum of Young Rats II. Origin of Microglial Cells. J. Comp. Neurol. 1978, 180, 139–163. [Google Scholar] [CrossRef] [PubMed]
  34. Bardehle, S.; Krüger, M.; Buggenthin, F.; Schwausch, J.; Ninkovic, J.; Clevers, H.; Snippert, H.J.; Theis, F.J.; Meyer-Luehmann, M.; Bechmann, I.; et al. Live Imaging of Astrocyte Responses to Acute Injury Reveals Selective Juxtavascular Proliferation. Nat. Neurosci. 2013, 16, 580–586. [Google Scholar] [CrossRef]
  35. Kiaie, N.; Gorabi, A.M.; Loveless, R.; Teng, Y.; Jamialahmadi, T.; Sahebkar, A. The Regenerative Potential of Glial Progenitor Cells and Reactive Astrocytes in CNS Injuries. Neurosci. Biobehav. Rev. 2022, 140, 104794. [Google Scholar] [CrossRef]
  36. Garzón-Muvdi, T.; Quiñones-Hinojosa, A. Neural Stem Cell Niches and Homing: Recruitment and Integration into Functional Tissues. ILAR J. 2010, 51, 3–23. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Lee, J.H.; Lee, J.E.; Kahng, J.Y.; Kim, S.H.; Park, J.S.; Yoon, S.J.; Um, J.-Y.; Kim, W.K.; Lee, J.-K.; Park, J.; et al. Human Glioblastoma Arises from Subventricular Zone Cells with Low-Level Driver Mutations. Nature 2018, 560, 243–247. [Google Scholar] [CrossRef]
  38. Amariglio, N.; Hirshberg, A.; Scheithauer, B.W.; Cohen, Y.; Loewenthal, R.; Trakhtenbrot, L.; Paz, N.; Koren-Michowitz, M.; Waldman, D.; Leider-Trejo, L.; et al. Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient. PLoS Med. 2009, 6, e1000029. [Google Scholar] [CrossRef]
  39. Sanai, N.; Tramontin, A.D.; Quiñones-Hinojosa, A.; Barbaro, N.M.; Gupta, N.; Kunwar, S.; Lawton, M.T.; McDermott, M.W.; Parsa, A.T.; Manuel-García Verdugo, J.; et al. Unique Astrocyte Ribbon in Adult Human Brain Contains Neural Stem Cells but Lacks Chain Migration. Nature 2004, 427, 740–744. [Google Scholar] [CrossRef]
  40. Doetsch, F.; García-Verdugo, J.M.; Alvarez-Buylla, A. Cellular Composition and Three-Dimensional Organization of the Subventricular Germinal Zone in the Adult Mammalian Brain. J. Neurosci. 1997, 17, 5046–5061. [Google Scholar] [CrossRef] [Green Version]
  41. Quiñones-Hinojosa, A.; Sanai, N.; Soriano-Navarro, M.; Gonzalez-Perez, O.; Mirzadeh, Z.; Gil-Perotin, S.; Romero-Rodriguez, R.; Berger, M.S.; Garcia-Verdugo, J.M.; Alvarez-Buylla, A. Cellular Composition and Cytoarchitecture of the Adult Human Subventricular Zone: A Niche of Neural Stem Cells. J. Comp. Neurol. 2006, 494, 415–434. [Google Scholar] [CrossRef] [PubMed]
  42. Ihrie, R.A.; Alvarez-Buylla, A. Cells in the Astroglial Lineage Are Neural Stem Cells. Cell Tissue Res. 2008, 331, 179–191. [Google Scholar] [CrossRef] [PubMed]
  43. Lois, C.; Alvarez-Buylla, A. Proliferating Subventricular Zone Cells in the Adult Mammalian Forebrain Can Differentiate into Neurons and Glia. Proc. Natl. Acad. Sci. USA 1993, 90, 2074–2077. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Guerrero-Cázares, H.; Gonzalez-Perez, O.; Soriano-Navarro, M.; Zamora-Berridi, G.; García-Verdugo, J.M.; Quinoñes-Hinojosa, A. Cytoarchitecture of the Lateral Ganglionic Eminence and Rostral Extension of the Lateral Ventricle in the Human Fetal Brain. J. Comp. Neurol. 2011, 519, 1165–1180. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Curtis, M.A.; Kam, M.; Nannmark, U.; Anderson, M.F.; Axell, M.Z.; Wikkelso, C.; Holtås, S.; van Roon-Mom, W.M.C.; Björk-Eriksson, T.; Nordborg, C.; et al. Human Neuroblasts Migrate to the Olfactory Bulb via a Lateral Ventricular Extension. Science 2007, 315, 1243–1249. [Google Scholar] [CrossRef]
  46. Kam, M.; Curtis, M.A.; McGlashan, S.R.; Connor, B.; Nannmark, U.; Faull, R.L.M. The Cellular Composition and Morphological Organization of the Rostral Migratory Stream in the Adult Human Brain. J. Chem. Neuroanat. 2009, 37, 196–205. [Google Scholar] [CrossRef] [PubMed]
  47. Sanai, N.; Nguyen, T.; Ihrie, R.A.; Mirzadeh, Z.; Tsai, H.-H.; Wong, M.; Gupta, N.; Berger, M.S.; Huang, E.; Garcia-Verdugo, J.-M.; et al. Corridors of Migrating Neurons in the Human Brain and Their Decline during Infancy. Nature 2011, 478, 382–386. [Google Scholar] [CrossRef] [Green Version]
  48. Paredes, M.F.; James, D.; Gil-Perotin, S.; Kim, H.; Cotter, J.A.; Ng, C.; Sandoval, K.; Rowitch, D.H.; Xu, D.; McQuillen, P.S.; et al. Extensive Migration of Young Neurons into the Infant Human Frontal Lobe. Science 2016, 354, aaf7073. [Google Scholar] [CrossRef] [Green Version]
  49. Ernst, A.; Alkass, K.; Bernard, S.; Salehpour, M.; Perl, S.; Tisdale, J.; Possnert, G.; Druid, H.; Frisén, J. Neurogenesis in the Striatum of the Adult Human Brain. Cell 2014, 156, 1072–1083. [Google Scholar] [CrossRef] [Green Version]
  50. MacLeod, G.; Bozek, D.A.; Rajakulendran, N.; Monteiro, V.; Ahmadi, M.; Steinhart, Z.; Kushida, M.M.; Yu, H.; Coutinho, F.J.; Cavalli, F.M.G.; et al. Genome-Wide CRISPR-Cas9 Screens Expose Genetic Vulnerabilities and Mechanisms of Temozolomide Sensitivity in Glioblastoma Stem Cells. Cell Rep. 2019, 27, 971–986.e9. [Google Scholar] [CrossRef] [Green Version]
  51. Thirant, C.; Galan-Moya, E.; Dubois, L.G.; Pinte, S.; Chafey, P.; Broussard, C.; Varlet, P.; Devaux, B.; Soncin, F.; Gavard, J.; et al. Differential Proteomic Analysis of Human Glioblastoma and Neural Stem Cells Reveals HDGF as a Novel Angiogenic Secreted Factor. Stem Cells 2012, 30, 845–853. [Google Scholar] [CrossRef] [PubMed]
  52. Lee, J.; Kotliarova, S.; Kotliarov, Y.; Li, A.; Su, Q.; Donin, N.M.; Pastorino, S.; Purow, B.W.; Christopher, N.; Zhang, W.; et al. Tumor Stem Cells Derived from Glioblastomas Cultured in BFGF and EGF More Closely Mirror the Phenotype and Genotype of Primary Tumors than Do Serum-Cultured Cell Lines. Cancer Cell 2006, 9, 391–403. [Google Scholar] [CrossRef] [Green Version]
  53. Gangemi, R.M.R.; Griffero, F.; Marubbi, D.; Perera, M.; Capra, M.C.; Malatesta, P.; Ravetti, G.L.; Zona, G.L.; Daga, A.; Corte, G. SOX2 Silencing in Glioblastoma Tumor-Initiating Cells Causes Stop of Proliferation and Loss of Tumorigenicity. Stem Cells 2009, 27, 40–48. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Zbinden, M.; Duquet, A.; Lorente-Trigos, A.; Ngwabyt, S.-N.; Borges, I.; Ruiz i Altaba, A. NANOG Regulates Glioma Stem Cells and Is Essential in Vivo Acting in a Cross-Functional Network with GLI1 and P53. EMBO J. 2010, 29, 2659–2674. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Clement, V.; Sanchez, P.; de Tribolet, N.; Radovanovic, I.; Ruiz i Altaba, A. HEDGEHOG-GLI1 Signaling Regulates Human Glioma Growth, Cancer Stem Cell Self-Renewal, and Tumorigenicity. Curr. Biol. 2007, 17, 165–172. [Google Scholar] [CrossRef] [PubMed]
  56. Bar, E.E.; Chaudhry, A.; Lin, A.; Fan, X.; Schreck, K.; Matsui, W.; Piccirillo, S.; Vescovi, A.L.; DiMeco, F.; Olivi, A.; et al. Cyclopamine-Mediated Hedgehog Pathway Inhibition Depletes Stem-Like Cancer Cells in Glioblastoma. Stem Cells 2007, 25, 2524–2533. [Google Scholar] [CrossRef] [Green Version]
  57. Xu, Q.; Yuan, X.; Liu, G.; Black, K.L.; Yu, J.S. Hedgehog Signaling Regulates Brain Tumor-Initiating Cell Proliferation and Portends Shorter Survival for Patients with PTEN-Coexpressing Glioblastomas. Stem Cells 2008, 26, 3018–3026. [Google Scholar] [CrossRef] [Green Version]
  58. Fareh, M.; Turchi, L.; Virolle, V.; Debruyne, D.; Almairac, F.; de-la-Forest Divonne, S.; Paquis, P.; Preynat-Seauve, O.; Krause, K.-H.; Chneiweiss, H.; et al. The MiR 302-367 Cluster Drastically Affects Self-Renewal and Infiltration Properties of Glioma-Initiating Cells through CXCR4 Repression and Consequent Disruption of the SHH-GLI-NANOG Network. Cell Death Differ. 2012, 19, 232–244. [Google Scholar] [CrossRef]
  59. Rieske, P.; Golanska, E.; Zakrzewska, M.; Piaskowski, S.; Hulas-Bigoszewska, K.; Wolańczyk, M.; Szybka, M.; Witusik-Perkowska, M.; Jaskolski, D.J.; Zakrzewski, K.; et al. Arrested Neural and Advanced Mesenchymal Differentiation of Glioblastoma Cells-Comparative Study with Neural Progenitors. BMC Cancer 2009, 9, 54. [Google Scholar] [CrossRef] [Green Version]
  60. Fan, X.; Khaki, L.; Zhu, T.S.; Soules, M.E.; Talsma, C.E.; Gul, N.; Koh, C.; Zhang, J.; Li, Y.-M.; Maciaczyk, J.; et al. NOTCH Pathway Blockade Depletes CD133-Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts. Stem Cells 2010, 28, 5–16. [Google Scholar] [CrossRef] [Green Version]
  61. Imayoshi, I.; Sakamoto, M.; Yamaguchi, M.; Mori, K.; Kageyama, R. Essential Roles of Notch Signaling in Maintenance of Neural Stem Cells in Developing and Adult Brains. J. Neurosci. 2010, 30, 3489–3498. [Google Scholar] [CrossRef] [Green Version]
  62. Panchision, D.M.; McKay, R.D.G. The Control of Neural Stem Cells by Morphogenic Signals. Curr. Opin. Genet. Dev. 2002, 12, 478–487. [Google Scholar] [CrossRef] [PubMed]
  63. Hall, A.K.; Miller, R.H. Emerging Roles for Bone Morphogenetic Proteins in Central Nervous System Glial Biology. J. Neurosci. Res. 2004, 76, 1–8. [Google Scholar] [CrossRef] [PubMed]
  64. Lim, D.A.; Tramontin, A.D.; Trevejo, J.M.; Herrera, D.G.; García-Verdugo, J.M.; Alvarez-Buylla, A. Noggin Antagonizes BMP Signaling to Create a Niche for Adult Neurogenesis. Neuron 2000, 28, 713–726. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Lee, J.; Son, M.J.; Woolard, K.; Donin, N.M.; Li, A.; Cheng, C.H.; Kotliarova, S.; Kotliarov, Y.; Walling, J.; Ahn, S.; et al. Epigenetic-Mediated Dysfunction of the Bone Morphogenetic Protein Pathway Inhibits Differentiation of Glioblastoma-Initiating Cells. Cancer Cell 2008, 13, 69–80. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Ferguson, K.M.; Blin, C.; Alfazema, N.; Gangoso, E.; Pollard, S.M.; Marques-Torrejon, M.A. Lrig1 Regulates the Balance between Proliferation and Quiescence in Glioblastoma Stem Cells. Front. Cell Dev. Biol. 2022, 10, 983097. [Google Scholar] [CrossRef]
  67. Marqués-Torrejón, M.Á.; Williams, C.A.C.; Southgate, B.; Alfazema, N.; Clements, M.P.; Garcia-Diaz, C.; Blin, C.; Arranz-Emparan, N.; Fraser, J.; Gammoh, N.; et al. LRIG1 Is a Gatekeeper to Exit from Quiescence in Adult Neural Stem Cells. Nat. Commun. 2021, 12, 2594. [Google Scholar] [CrossRef]
  68. Kaur, N.; Chettiar, S.; Rathod, S.; Rath, P.; Muzumdar, D.; Shaikh, M.L.; Shiras, A. Wnt3a Mediated Activation of Wnt/β-Catenin Signaling Promotes Tumor Progression in Glioblastoma. Mol. Cell. Neurosci. 2013, 54, 44–57. [Google Scholar] [CrossRef]
  69. Ming, G.; Song, H. Adult Neurogenesis in the Mammalian Central Nervous System. Annu. Rev. Neurosci. 2005, 28, 223–250. [Google Scholar] [CrossRef]
  70. Ahn, S.; Joyner, A.L. In Vivo Analysis of Quiescent Adult Neural Stem Cells Responding to Sonic Hedgehog. Nature 2005, 437, 894–897. [Google Scholar] [CrossRef]
  71. de la Iglesia, N.; Konopka, G.; Puram, S.V.; Chan, J.A.; Bachoo, R.M.; You, M.J.; Levy, D.E.; DePinho, R.A.; Bonni, A. Identification of a PTEN-Regulated STAT3 Brain Tumor Suppressor Pathway. Genes Dev. 2008, 22, 449–462. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Sherry, M.M.; Reeves, A.; Wu, J.K.; Cochran, B.H. STAT3 Is Required for Proliferation and Maintenance of Multipotency in Glioblastoma Stem Cells. Stem Cells 2009, 27, 2383–2392. [Google Scholar] [CrossRef] [Green Version]
  73. Surena, A.-L.; de Faria, G.P.; Studler, J.-M.; Peiretti, F.; Pidoux, M.; Camonis, J.; Chneiweiss, H.; Formstecher, E.; Junier, M.-P. DLG1/SAP97 Modulates Transforming Growth Factor α Bioavailability. Biochim. Biophys. Acta BBA-Mol. Cell Res. 2009, 1793, 264–272. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Toyoda, K.; Tanaka, K.; Nakagawa, S.; Thuy, D.H.D.; Ujifuku, K.; Kamada, K.; Hayashi, K.; Matsuo, T.; Nagata, I.; Niwa, M. Initial Contact of Glioblastoma Cells with Existing Normal Brain Endothelial Cells Strengthen the Barrier Function via Fibroblast Growth Factor 2 Secretion: A New In Vitro Blood–Brain Barrier Model. Cell. Mol. Neurobiol. 2013, 33, 489–501. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Treps, L.; Perret, R.; Edmond, S.; Ricard, D.; Gavard, J. Glioblastoma Stem-like Cells Secrete the pro-Angiogenic VEGF-A Factor in Extracellular Vesicles. J. Extracell. Vesicles 2017, 6, 1359479. [Google Scholar] [CrossRef] [Green Version]
  76. Li, G.; Chen, Z.; Hu, Y.-D.; Wei, H.; Li, D.; Ji, H.; Wang, D.-L. Autocrine Factors Sustain Glioblastoma Stem Cell Self-Renewal. Oncol. Rep. 2009, 21, 419–424. [Google Scholar]
  77. Bao, S.; Wu, Q.; Sathornsumetee, S.; Hao, Y.; Li, Z.; Hjelmeland, A.B.; Shi, Q.; McLendon, R.E.; Bigner, D.D.; Rich, J.N. Stem Cell–like Glioma Cells Promote Tumor Angiogenesis through Vascular Endothelial Growth Factor. Cancer Res. 2006, 66, 7843–7848. [Google Scholar] [CrossRef] [Green Version]
  78. El-Obeid, A.; Bongcam-Rudloff, E.; Sörby, M.; Ostman, A.; Nistér, M.; Westermark, B. Cell Scattering and Migration Induced by Autocrine Transforming Growth Factor Alpha in Human Glioma Cells in Vitro. Cancer Res. 1997, 57, 5598–5604. [Google Scholar]
  79. Lichti, C.F.; Liu, H.; Shavkunov, A.S.; Mostovenko, E.; Sulman, E.P.; Ezhilarasan, R.; Wang, Q.; Kroes, R.A.; Moskal, J.C.; Fenyö, D.; et al. Integrated Chromosome 19 Transcriptomic and Proteomic Data Sets Derived from Glioma Cancer Stem-Cell Lines. J. Proteome Res. 2014, 13, 191–199. [Google Scholar] [CrossRef]
  80. Mughal, A.A.; Zhang, L.; Fayzullin, A.; Server, A.; Li, Y.; Wu, Y.; Glass, R.; Meling, T.; Langmoen, I.A.; Leergaard, T.B.; et al. Patterns of Invasive Growth in Malignant Gliomas—The Hippocampus Emerges as an Invasion-Spared Brain Region. Neoplasia 2018, 20, 643–656. [Google Scholar] [CrossRef]
  81. Bergmann, O.; Liebl, J.; Bernard, S.; Alkass, K.; Yeung, M.S.Y.; Steier, P.; Kutschera, W.; Johnson, L.; Landén, M.; Druid, H.; et al. The Age of Olfactory Bulb Neurons in Humans. Neuron 2012, 74, 634–639. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Qin, E.Y.; Cooper, D.D.; Abbott, K.L.; Lennon, J.; Nagaraja, S.; Mackay, A.; Jones, C.; Vogel, H.; Jackson, P.K.; Monje, M. Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma. Cell 2017, 170, 845–859.e19. [Google Scholar] [CrossRef] [PubMed]
  83. Zappaterra, M.W.; Lehtinen, M.K. The Cerebrospinal Fluid: Regulator of Neurogenesis, Behavior, and Beyond. Cell. Mol. Life Sci. 2012, 69, 2863–2878. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Carrano, A.; Zarco, N.; Phillipps, J.; Lara-Velazquez, M.; Suarez-Meade, P.; Norton, E.S.; Chaichana, K.L.; Quiñones-Hinojosa, A.; Asmann, Y.W.; Guerrero-Cázares, H. Human Cerebrospinal Fluid Modulates Pathways Promoting Glioblastoma Malignancy. Front. Oncol. 2021, 11, 624145. [Google Scholar] [CrossRef] [PubMed]
  85. Li, D.; Takeda, N.; Jain, R.; Manderfield, L.J.; Liu, F.; Li, L.; Anderson, S.A.; Epstein, J.A. Hopx Distinguishes Hippocampal from Lateral Ventricle Neural Stem Cells. Stem Cell Res. 2015, 15, 522–529. [Google Scholar] [CrossRef] [Green Version]
  86. Er, M.; Am, P. Neural Stem Cells of the Subventricular Zone as the Origin of Human Glioblastoma Stem Cells. Therapeutic Implications. Front. Oncol. 2019, 9, 779. [Google Scholar] [CrossRef] [Green Version]
  87. Galli, R.; Binda, E.; Orfanelli, U.; Cipelletti, B.; Gritti, A.; De Vitis, S.; Fiocco, R.; Foroni, C.; Dimeco, F.; Vescovi, A. Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma. Cancer Res. 2004, 64, 7011–7021. [Google Scholar] [CrossRef] [Green Version]
  88. Zhu, Y.; Guignard, F.; Zhao, D.; Liu, L.; Burns, D.K.; Mason, R.P.; Messing, A.; Parada, L.F. Early Inactivation of P53 Tumor Suppressor Gene Cooperating with NF1 Loss Induces Malignant Astrocytoma. Cancer Cell 2005, 8, 119–130. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Alcantara Llaguno, S.R.; Xie, X.; Parada, L.F. Cell of Origin and Cancer Stem Cells in Tumor Suppressor Mouse Models of Glioblastoma. Cold Spring Harb. Symp. Quant. Biol. 2016, 81, 31–36. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Lee, M.; Kim, Y.-S.; Lee, K.; Kang, M.; Shin, H.; Oh, J.-W.; Koo, H.; Kim, D.; Kim, Y.; Kong, D.-S.; et al. Novel Semi-Replicative Retroviral Vector Mediated Double Suicide Gene Transfer Enhances Antitumor Effects in Patient-Derived Glioblastoma Models. Cancers 2019, 11, 1090. [Google Scholar] [CrossRef] [Green Version]
  91. Holland, E.C.; Celestino, J.; Dai, C.; Schaefer, L.; Sawaya, R.E.; Fuller, G.N. Combined Activation of Ras and Akt in Neural Progenitors Induces Glioblastoma Formation in Mice. Nat. Genet. 2000, 25, 55–57. [Google Scholar] [CrossRef]
  92. Jacques, T.S.; Swales, A.; Brzozowski, M.J.; Henriquez, N.V.; Linehan, J.M.; Mirzadeh, Z.; O’ Malley, C.; Naumann, H.; Alvarez-Buylla, A.; Brandner, S. Combinations of Genetic Mutations in the Adult Neural Stem Cell Compartment Determine Brain Tumour Phenotypes. EMBO J. 2010, 29, 222–235. [Google Scholar] [CrossRef] [Green Version]
  93. Alcantara Llaguno, S.; Chen, J.; Kwon, C.-H.; Jackson, E.L.; Li, Y.; Burns, D.K.; Alvarez-Buylla, A.; Parada, L.F. Malignant Astrocytomas Originate from Neural Stem/Progenitor Cells in a Somatic Tumor Suppressor Mouse Model. Cancer Cell 2009, 15, 45–56. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Ignatova, T.N.; Kukekov, V.G.; Laywell, E.D.; Suslov, O.N.; Vrionis, F.D.; Steindler, D.A. Human Cortical Glial Tumors Contain Neural Stem-like Cells Expressing Astroglial and Neuronal Markers in Vitro. Glia 2002, 39, 193–206. [Google Scholar] [CrossRef]
  95. Jafri, N.F.; Clarke, J.L.; Weinberg, V.; Barani, I.J.; Cha, S. Relationship of Glioblastoma Multiforme to the Subventricular Zone Is Associated with Survival. Neuro-Oncology 2013, 15, 91–96. [Google Scholar] [CrossRef] [Green Version]
  96. Adeberg, S.; Bostel, T.; König, L.; Welzel, T.; Debus, J.; Combs, S.E. A Comparison of Long-Term Survivors and Short-Term Survivors with Glioblastoma, Subventricular Zone Involvement: A Predictive Factor for Survival? Radiat. Oncol. 2014, 9, 95. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Lim, D.A.; Cha, S.; Mayo, M.C.; Chen, M.-H.; Keles, E.; VandenBerg, S.; Berger, M.S. Relationship of Glioblastoma Multiforme to Neural Stem Cell Regions Predicts Invasive and Multifocal Tumor Phenotype. Neuro-Oncology 2007, 9, 424–429. [Google Scholar] [CrossRef]
  98. Berger, F.; Gay, E.; Pelletier, L.; Tropel, P.; Wion, D. Development of Gliomas: Potential Role of Asymmetrical Cell Division of Neural Stem Cells. Lancet Oncol. 2004, 5, 511–514. [Google Scholar] [CrossRef] [PubMed]
  99. Vescovi, A.L.; Galli, R.; Reynolds, B.A. Brain Tumour Stem Cells. Nat. Rev. Cancer 2006, 6, 425–436. [Google Scholar] [CrossRef]
  100. Quiñones-Hinojosa, A.; Chaichana, K. The Human Subventricular Zone: A Source of New Cells and a Potential Source of Brain Tumors. Exp. Neurol. 2007, 205, 313–324. [Google Scholar] [CrossRef]
  101. Lai, A.; Kharbanda, S.; Pope, W.B.; Tran, A.; Solis, O.E.; Peale, F.; Forrest, W.F.; Pujara, K.; Carrillo, J.A.; Pandita, A.; et al. Evidence for Sequenced Molecular Evolution of IDH1 Mutant Glioblastoma From a Distinct Cell of Origin. J. Clin. Oncol. 2011, 29, 4482–4490. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Canoll, P.; Goldman, J.E. The Interface between Glial Progenitors and Gliomas. Acta Neuropathol. 2008, 116, 465–477. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Hou, L.C.; Veeravagu, A.; Hsu, A.R.; Tse, V.C.K. Recurrent Glioblastoma Multiforme: A Review of Natural History and Management Options. Neurosurg. Focus 2006, 20, E3. [Google Scholar] [CrossRef] [PubMed]
  104. Liotta, L.A.; Kohn, E.C. The Microenvironment of the Tumour–Host Interface. Nature 2001, 411, 375–379. [Google Scholar] [CrossRef] [PubMed]
  105. Aboody, K.S.; Brown, A.; Rainov, N.G.; Bower, K.A.; Liu, S.; Yang, W.; Small, J.E.; Herrlinger, U.; Ourednik, V.; Black, P.M.; et al. Neural Stem Cells Display Extensive Tropism for Pathology in Adult Brain: Evidence from Intracranial Gliomas. Proc. Natl. Acad. Sci. USA 2000, 97, 12846–12851. [Google Scholar] [CrossRef] [Green Version]
  106. Assanah, M.; Lochhead, R.; Ogden, A.; Bruce, J.; Goldman, J.; Canoll, P. Glial Progenitors in Adult White Matter Are Driven to Form Malignant Gliomas by Platelet-Derived Growth Factor-Expressing Retroviruses. J. Neurosci. 2006, 26, 6781–6790. [Google Scholar] [CrossRef] [Green Version]
  107. Li, S.; Gao, Y.; Tokuyama, T.; Yamamoto, J.; Yokota, N.; Yamamoto, S.; Terakawa, S.; Kitagawa, M.; Namba, H. Genetically Engineered Neural Stem Cells Migrate and Suppress Glioma Cell Growth at Distant Intracranial Sites. Cancer Lett. 2007, 251, 220–227. [Google Scholar] [CrossRef]
  108. Kim, S.-K.; Kim, S.U.; Park, I.H.; Bang, J.H.; Aboody, K.S.; Wang, K.-C.; Cho, B.-K.; Kim, M.; Menon, L.G.; Black, P.M.; et al. Human Neural Stem Cells Target Experimental Intracranial Medulloblastoma and Deliver a Therapeutic Gene Leading to Tumor Regression. Clin. Cancer Res. 2006, 12, 5550–5556. [Google Scholar] [CrossRef] [Green Version]
  109. Liu, C.; Zong, H. Developmental Origins of Brain Tumors. Curr. Opin. Neurobiol. 2012, 22, 844–849. [Google Scholar] [CrossRef] [Green Version]
  110. Cahoy, J.D.; Emery, B.; Kaushal, A.; Foo, L.C.; Zamanian, J.L.; Christopherson, K.S.; Xing, Y.; Lubischer, J.L.; Krieg, P.A.; Krupenko, S.A.; et al. A Transcriptome Database for Astrocytes, Neurons, and Oligodendrocytes: A New Resource for Understanding Brain Development and Function. J. Neurosci. 2008, 28, 264–278. [Google Scholar] [CrossRef] [Green Version]
  111. Kupp, R.; Shtayer, L.; Tien, A.-C.; Szeto, E.; Sanai, N.; Rowitch, D.H.; Mehta, S. Lineage-Restricted OLIG2-RTK Signaling Governs the Molecular Subtype of Glioma Stem-like Cells. Cell Rep. 2016, 16, 2838–2845. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Carén, H.; Stricker, S.H.; Bulstrode, H.; Gagrica, S.; Johnstone, E.; Bartlett, T.E.; Feber, A.; Wilson, G.; Teschendorff, A.E.; Bertone, P.; et al. Glioblastoma Stem Cells Respond to Differentiation Cues but Fail to Undergo Commitment and Terminal Cell-Cycle Arrest. Stem Cell Rep. 2015, 5, 829–842. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Park, N.I.; Guilhamon, P.; Desai, K.; McAdam, R.F.; Langille, E.; O’Connor, M.; Lan, X.; Whetstone, H.; Coutinho, F.J.; Vanner, R.J.; et al. ASCL1 Reorganizes Chromatin to Direct Neuronal Fate and Suppress Tumorigenicity of Glioblastoma Stem Cells. Cell Stem Cell 2017, 21, 209–224.e7. [Google Scholar] [CrossRef] [PubMed]
  114. Zong, H.; Verhaak, R.G.; Canoll, P. The Cellular Origin for Malignant Glioma and Prospects for Clinical Advancements. Expert Rev. Mol. Diagn. 2012, 12, 383–394. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Ghosh, D.; Funk, C.C.; Caballero, J.; Shah, N.; Rouleau, K.; Earls, J.C.; Soroceanu, L.; Foltz, G.; Cobbs, C.S.; Price, N.D.; et al. A Cell-Surface Membrane Protein Signature for Glioblastoma. Cell Syst. 2017, 4, 516–529.e7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Figure 1. The glioma cell of origin. NSCs are undifferentiated cells with self-renewal and multipotent capacities. They give rise to neurons, astrocytes, and OPCs. NSCs can be mutated and converted into glioma stem cells (GSCs).
Figure 1. The glioma cell of origin. NSCs are undifferentiated cells with self-renewal and multipotent capacities. They give rise to neurons, astrocytes, and OPCs. NSCs can be mutated and converted into glioma stem cells (GSCs).
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Figure 2. The adult human SVZ. (I) Illustration of the adult human SVZ and adjacent GBM. Left panel shows a drawing with the four layers of the human SVZ (I–IV) and an adjacent GBM close to this area. Ependymal layer (layer I) is lining the lateral ventricle. NSCs are represented in navy blue. These cells are in contact with the CSF and blood vessels (BV). NSCs could acquire driver mutations, become GSCs, and generate the tumor mass (red mass). (II) A patient was diagnosed with IDH1 wild-type GBM by biopsy and is showing an early contrast-enhanced axial T1-weighted MRI with non-enhancing areas (A), and a small hyperintensity in FLAIR sequence imaging located in the lateral wall of the right lateral ventricle (B). After a month, we can observe progression of the tumor, with an increase in T1 contrast enhancement (C).
Figure 2. The adult human SVZ. (I) Illustration of the adult human SVZ and adjacent GBM. Left panel shows a drawing with the four layers of the human SVZ (I–IV) and an adjacent GBM close to this area. Ependymal layer (layer I) is lining the lateral ventricle. NSCs are represented in navy blue. These cells are in contact with the CSF and blood vessels (BV). NSCs could acquire driver mutations, become GSCs, and generate the tumor mass (red mass). (II) A patient was diagnosed with IDH1 wild-type GBM by biopsy and is showing an early contrast-enhanced axial T1-weighted MRI with non-enhancing areas (A), and a small hyperintensity in FLAIR sequence imaging located in the lateral wall of the right lateral ventricle (B). After a month, we can observe progression of the tumor, with an increase in T1 contrast enhancement (C).
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Loras, A.; Gonzalez-Bonet, L.G.; Gutierrez-Arroyo, J.L.; Martinez-Cadenas, C.; Marques-Torrejon, M.A. Neural Stem Cells as Potential Glioblastoma Cells of Origin. Life 2023, 13, 905.

AMA Style

Loras A, Gonzalez-Bonet LG, Gutierrez-Arroyo JL, Martinez-Cadenas C, Marques-Torrejon MA. Neural Stem Cells as Potential Glioblastoma Cells of Origin. Life. 2023; 13(4):905.

Chicago/Turabian Style

Loras, Alba, Luis G. Gonzalez-Bonet, Julia L. Gutierrez-Arroyo, Conrado Martinez-Cadenas, and Maria Angeles Marques-Torrejon. 2023. "Neural Stem Cells as Potential Glioblastoma Cells of Origin" Life 13, no. 4: 905.

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