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Glioblastoma Stem Cells and Tumor Microenvironment: Comparison
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Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Anica Dricu.

Glioblastoma stem cells (GSCs) are cells with a self-renewal ability and capacity to initiate tumors upon serial transplantation that have been linked to tumor cell heterogeneity. Most standard treatments fail to completely eradicate GSCs, causing the recurrence of the disease. GSCs could represent one reason for the low efficacy of cancer therapy and for the short relapse time. Nonetheless, experimental data suggest that the presence of therapy‐resistant GSCs could explain tumor recurrence. Therefore, to effectively target GSCs, a comprehensive understanding of their biology and the survival and developing mechanisms during treatment is mandatory. This review provides an overview of the molecular features, microenvironment, detection, and targeting strategies of GSCs, an essential information required for an efficient therapy. Despite the outstanding results in oncology, researchers are still developing novel strategies, of which one could be targeting the GSCs present in the hypoxic regions and invasive edge of the glioblastoma. 

  • glioblastoma
  • stem cell
  • growth factor

1. Introduction

Glioblastoma (GBM) is the most common type of primary malignant brain tumor, accounting for 55% of primary brain tumors. GBM has a poor prognosis, with a mean survival rate between 14 to 16 months for patients treated with the standard treatment strategies (maximal safe surgical resection, followed by radiotherapy together with concomitant and adjuvant chemotherapy using temozolomide (TMZ)). Temozolomide is the first-line chemotherapy drug in GBM, an available orally alkylating agent that causes apoptosis by generating single-strand and double-strand breaks in DNA [1]. The 2-year survival rate was still less than 30%, even in the most recent reports.
GBM is a heterogeneous tumor resistant to all therapeutic approaches because of the multiple subclonal driver mutations [2,3][2][3]. Almost all tumors consist of various cell populations and heterogeneity that make them difficult to treat. The causes of recurrence are complex and include the absence of a clear tumor margin useful for a complete resection, the presence of migrating cancer cells into the surrounding normal tissue, high proliferative index, chemotherapy and radiotherapy resistance of the cancer stem cells (CSCs), and cerebrospinal fluid (CSF) dissemination. CSCs, also known as tumor-initiating cells (TICs), are suggested to be responsible for cancer relapse and drug resistance due to their ability to self-renew and to differentiate into a heterogeneous population of cancer cells [4,5][4][5].
Therefore, the surgical removal of the entire tumor mass is impossible. The presence of tumor cells at 2–3 cm from the original site of the tumor has led to even more aggressive tumoral recurrences after the removal of the tumor mass [6,7][6][7].
TICs and GSCs represent a subpopulation of self-renewing cells involved in the process of tumor initiation (for TICs) and tumor maintenance (for GSCs). Both types have distinct markers and biological functions and can be approached using different molecular and cellular methods. GSCs may be derived from TICs [8].
TICs (referred to as the cell of origin) are normal cells that acquire the first mutation that results in cancer promotion. The cells that promote GBM regrowth after surgical resection are supposed to be the undifferentiated GSCs, which produce differentiated progeny, creating a rapidly dividing tumor. They are also responsible for tumor heterogeneity and therapy resistance [9,10,11,12][9][10][11][12]. These cells demonstrate the main characteristics of stem cells: proliferation, differentiation, and self-renewal [9,13,14][9][13][14].
The GSCs’ resistance to radio- and chemotherapy could be explained by their high capacity for extensive DNA repair, quiescence, higher mitochondrial reserve, and localization in the hypoxic niche [9]. Mitochondrial activity is modulated by hypoxic conditions, controlling cell apoptosis and necroptosis, and reactive oxygen species (ROS) generation, therefore reducing susceptibility to chemo- and radio-induced apoptosis [15,16][15][16]. Moreover, anticancer therapies induce cell death by direct or indirect DNA damage. Targeting the DNA repairing pathways could increase the sensitivity of tumor to various cancer therapies [17]. Quiescence is a mechanism that turns the stem cells into a low metabolic state. The quiescence is correlated with the tumor microenvironment, including the extracellular matrix, immune cells, signaling molecules, and surrounding blood vessels. In GSCs, low ROS levels are associated with the quiescence/dormancy state of stem cells and with a protective intracellular environment [18].
Furthermore, integrated algorithms based on IHC can offer high accuracy in predicting glioblastoma transcriptional subtypes. In a study published by Orzan et al., mesenchymal and classical subgroups proved to be well segregated, and the proneural types showed a mixed proneural/classical phenotype, predicted by the algorithm as proneural, but with comparable probability to be a part of a classical subtype [22][19].
The tissue is protected from harmful molecules by the existence of the blood–brain barrier (BBB) [23][20]. This is formed by astrocytes and pericytes that surround the endothelial cell tight junctions [24][21]. Due to the existence of this barrier, the delivery of effective drug concentration is sometimes difficult, as it regulates the extravasation of macromolecules and chemotherapy drugs [24][21]. Because of the high genetic heterogeneity [25[22][23][24],26,27], it is impossible to target all GBM cells using only one biomarker-targeted therapy. Most of the GSCs are found in the hypoxic and necrotic areas, which are difficult to penetrate by the chemotherapy drugs. Furthermore, their resistance to chemotherapy is facilitated by various mechanisms, such as drug metabolic inactivation, decreased drug influx, overexpression of drug efflux pumps, slow division rate, inhibition of prodrug to bioactive drug conversion, and increased double-strand DNA repair [9,28,29,30][9][25][26][27]. The mechanism of the drug efflux is energy dependent, and it is facilitated by the increased expression of the ATP-binding cassette superfamily (ABC) of transporters [31][28], which are overexpressed in GSCs [32][29].
Aldehyde dehydrogenase 1 (ALDH), an enzyme that detoxifies alkylating agents, reducing their reactivity, and O6-methylguanine-DNA methyltransferase (MGMT), a detoxifier enzyme, are both contributors to GBM chemoresistance and highly expressed by GSCs [33,34,35][30][31][32].
ALDHs are markers of CSCs indicating worse prognosis in GBM [36][33]. ALDHs have not been proved to be linked to DNA repairing pathways, and the mechanism of how they mediate chemoresistance remains unclear. Clinical data reported increased levels of ALDH1A3 in recurrent GBM tumors [35][32]. It has been proved that ALDH1A3 is involved in ROS reaction. ROS react with polyunsaturated fatty acids from lipid membranes, inducing lipid peroxidation. ALDH1A3 seems to reduce the extent of toxic aldehydes resulting from lipid peroxidation [37][34].
Nevertheless, MGMT is directly responsible for the repair of lesion. Epigenetic silencing of the MGMT gene inhibits the synthesis of MGMT, increasing the sensitivity to cytotoxic effects induced by alkylating compounds. MGMT methylation is a predictor of longer survival for diagnosis but not for recurrence, suggesting that other mechanisms are responsible for MGMT upregulation in recurrent tumors [38][35]. Metastatic mismatch repair gene (MMR) alterations have been described in 10% to 20% of recurrent tumors, but changes in its promoter methylation status have been detected in a few patients [3]. It has been suggested that enhancer hijacking in recurrent GBMs could promote the MGMT expression and, therefore, alkylating compounds’ resistance, but this clinical significance remains to be evaluated [38,39][35][36].
Nonetheless, it has been demonstrated that radiotherapy is also insufficiently effective in destroying the GSCs [40,41][37][38]. Because of their high resistance to drugs, radiation, and surgery, the GSCs represent an important therapeutic target, intensively studied worldwide in the last years [41][38].

2. Glioblastoma SCstem Cells (GSCs) ’ Biomarkers

In order to achieve an optimum treatment efficacy, it is important to identify the GSCs from the rest of the tumoral cells. Glioblastoma stem cells present several biomarkers used for identification, such as CD133, nestin, musashi-1, CXCR4, CD15, CD34, CD44, SOX2, L1CAM, and A2B5, however, neither being exclusively characteristic for GSCs [42,43,44,45,46,47,48,49,50,51,52,53,54][39][40][41][42][43][44][45][46][47][48][49][50][51] (Table 1). Furthermore, this task becomes even more difficult because GBMs have the ability to remodel their microenvironment by modulating the immune system, vasculature, and stroma [44][41].
Table 1.
Biomarkers of GSCs.
Marker Category Origin Involved in Reference
CD133/Prominin Pantaspanglycoprotein family Hematopoietic stem cells, endothelial progenitors, myogenic cells, and stem cells Cell proliferation, migration, stem-cell-adjacent cell interactions [45][42]
CD34 Transmembrane glycoprotein Progenitor cells Cell–cell adhesion, migration, hematopoietic stem cell attachment to the extracellular matrix [46][43]
63]. GBMs are characterized by increased angiogenesis (process of stimulating the formation of new vessels from pre-existing ones) [2,4,5,9,13][2][4][5][9][13].
The perivascular niche is formed by nonmalignant cells (astrocytes, fibroblasts, pericytes, immune cells, neural progenitor cells) and malignant cells (GSCs and tumor cells located around disorganized blood vessels) [62][59]. These cells interact between them, supporting GSCs’ survival and growth. Under hypoxic conditions, the tumor produces angiogenic factors involved in the formation of the tumoral blood vessels.
More than 2 decades ago, the glioma proliferation was linked to growth factors and their receptors [67,68][64][65]. These factors include epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), mammalian target of rapamycin (mTOR), protein kinase C (PKC), histone deacetylase, farnesyltransferase, heat shock protein 90 (Hsp90), and histone deacetylase [69][66]. They are important mediators of angiogenesis, affecting the oxygen supply to tumors [70,71][67][68].
A variety of inhibitors became available (Table 2), and their effectiveness was demonstrated on glioblastoma using in vitro and in vivo studies [72,73,74,75,76,77,78,79,80,81,82][69][70][71][72][73][74][75][76][77][78][79].
Table 2.
Targeted therapies in glioblastoma.
Target Inhibitors References
αvβ3 and αvβ5 integrin Cilengitide [72][69]
EGFR Erlotinib, gefitinib, lapatinib, cetuximab, AEE788, EKB569, ZD6474 [73][70]
CD44 Glycoprotein Stem cells Adhesion in stem cell homing [47,48][44][45]
PDGFR Imatinib mesylate, sorafenib, SU011248, PTK787 [74][71] CD15 (SSEA-1) Trisaccharide Developing neural stem cells and subventricular zone Diagnosis as specific progenitor cell marker
VEGFR Sorafenib, valatanib, sunitinib, AEE788, AZD2171, ZD6474 [75][72][49,50][46][47]
Musashi-1 RNA-binding protein Neural stem cells Inhibiting the mRNAs’ translation [51
mTOR Temsirolimus, everolimus, sirolimus, AP23573 [76].[73].][48]
Nestin Intermediate filament Mammalian CNS stem cells during development Tumor cell growth, metastasis, and GSCs’ self-renewal [52]
PKC Tamoxifen, enzastaurin [77].[74].[49]
SOX2 and HMG box DNA-binding protein
Histone deacetylase Depsipeptide, suberoylanilide hydroxamic acidMultipotent neural stem cells and embryonic stem cells [78].[75].Sustaining neural and embryonic stem cell pluripotency [53][50]
L1CAM (CD171) Glycoprotein Neural cells Tumor growth, GSCs’ radiosensitivity, and DNA damage response regulation [54][51]

3. GSCs and Tumor Microenvironment

Even though several hypotheses have been proposed, none can fully explain the origin of the GBM. These hypotheses are based on the dedifferentiation of neural cells, transformation of undifferentiated precursor cells, and proliferation of neural stem cells [55,56,57][52][53][54]. Campos et al. stated that dedifferentiation may occur when an accumulation of genetic mutations in oncogenes appears in normal brain cells [58][55]. Additionally, genetic mutations in neural stem cells may cause the formation of cancer cells.
It seems that GSCs increase tumorigenesis by recapitulating the normal neural lineage hierarchies of quiescence and self-renewal. By maintaining stemness in specialized niches and by directing differentiation on the appropriate lineages, the microenvironment is controlling the normal neural stem cells’ fate. While GSCs are found in hypoxic and perivascular regions of the tumor bulk, not much is known about the GSCs’ differentiation potential within tumors and neither whether a prodifferentiative niche exists [59][56].
GBM may develop in the white matter and spread inside the brain via myelinated fibers, but the cellular and molecular processes that support the white matter invasion remain unknown. However, there are studies that revealed that the white matter may suppress malignancy by directing the differentiation of GSCs towards preoligodendrocyte fate [60][57].
Neural stem cells have two places of origin (also called neurogenic niches): the subventricular zone, located in the forebrain lateral ventricle, and the subgranular zone, located in the hippocampus in the dentate gyrus. Stem cells in quiescent or active mitotic state can be found in both regions [61][58].
Three major microenvironments have been described in glioblastoma: the hypoxic niche (around the necrotic core), the perivascular niche, and the invasive edge [62][59].

3.1. The Perivascular Niche

Vasculogenesis is the process of de novo formation of blood vessels that occurs mostly during fetal development. Studies showed that circulating endothelial cells, tumor-associated macrophages (TAMs), Tie-2 monocytes, myeloid-derived suppressor cells (MDSCs), neutrophiles, and GSCs are involved in the formation of new vessels [63,64,65,66][60][61][62][
Farnesyltransferase
Lonafarnib, tipifarnib
[
79
][76]
Hsp90 17-AAG [80][77]
Histone deacetylase Depsipeptide, suberoylanilide hydroxamic acid [81][78]
Proteasome Bortezomib [82][79]
Furthermore, GBM presents abnormal and fragile blood vessels. The rupture of the vessels leads to the disruption of the BBB [58][55]. These vessels are the result of the VEGF involvement in pericyte disintegration. After BBB disruption, tumor-derived chemokines attract immunomodulatory cells that enter the brain. They increase the angiogenic factors’ production, suppressing the immune function and leading to tumor progression [62][59]. Vascular pericytes attach to endothelial cells and play an important role in maintaining the BBB. The depletion of pericyte may disrupt the BBB and may elevate the vascular permeability [83][80]. In GBM, most of vascular pericytes derive from GSCs via transdifferentiation. They express tumor-specific genetic alterations, differentiating them from normal pericytes; therefore, the neovasculature and tumor growth may be potently inhibited by selective elimination of these GSC-derived pericytes. GSCs are recruited through the SDF-1/CXCR4 axis and are further induced to transform into pericytes by transforming growth factor β (TGF-β). However, GSCs may actively remodel perivascular niches by their contribution to vascular pericytes [84][81].
Different immune-suppressive mechanisms are used in GBM to prevent its immune detection and eradication. GBM cells secrete a variety of immunosuppressive proteins. Intracellular adhesion molecule 1 (ICAM-1) is a cell–cell interaction key regulator that is commonly upregulated in GBM. ICAM-1 promotes the migration of myeloid cells into tumors by interacting with lymphocyte function-associated antigen 1 (LFA-1) expressed on these cells. The accumulation of MDSC in GBM further contributes to immune suppression. Additionally, GBM overexpresses galectin-1 (Gal-1), which promotes tumor cell proliferation and migration [85][82].
Furthermore, regulatory T cells (Tregs) that either can originate in the thymus (naturally occurring Tregs) or can be induced by antigens (iTregs) could contribute to GBM-mediated immune suppression. Tregs suppress the immune responses by cytokine secretion, such as interleukin (IL)-10 and TGF-β, or by cell-to-cell mediated contact. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is present on the surface of activated T effector cells. Together with CTLA-4, programmed death 1 (PD-1) is an immune checkpoint that forms a system that regulates the immune activation and proliferation. Studies of tumor microenvironments revealed that this system is capable of inducing T-cell apoptosis [86,87,88][83][84][85].
TAMs play a significant role in the perivascular niche. TAMs are attracted in the niche by GSCs’ secreted periostin [93][86]. They produce heme-oxygenase 1 (HO-1) and thymidine phosphorylase (TP) involved in neovascularization. They express chemoattractants, such as VEGF, interleukin (IL)-6, colony-stimulating factor (CSF), stromal cell-derived factor 1α (SDF-1α), and IL-1β. The attraction of macrophages and monocytes generates an immunosuppressive phenotype and tumor progression. Additionally, TAMs produce TGF-β involved in matrix metalloproteinase 9 (MMP9) expression. This process causes further GSC proliferation [94][87].
The vasculature and angiogenic factors play a pivotal role in glioblastoma induction and the maintenance of immunosuppression. Proinflammatory repolarization of macrophages in the perivascular and perinecrotic tumor is probably an option to overcome treatment resistance [95][88].
Similar to VEGF and CSF, the CD34 role has been discussed in the diagnosis of various cancer pathologies. It has been demonstrated that it is involved in promoting a new blood vessel network and in increasing the nutrients and oxygen supply for further tumor growth [96][89]. In GBM, CD34 has been found to be expressed in the tumor vascular endothelial cell membrane. In gliomas, the CD34-positive cells are recruited by bone-marrow-derived circulating hematopoietic progenitors. In ourthe recent study, weresearch, researchers found no correlation between different grades of glioma or tumor vascularization and CD34 expression and with mild distribution of CD34 in CNS tumors [97][90]. Four types of CD34-labeled microvessel formations in glioblastomas have been detected based on different vascular niche pathologic structures: microvascular sprouting, vascular cluster, vascular garland, and glomeruloid vascular proliferation [98][91].
Targeting the perivascular niche could represent an effective approach for GBM therapy by using angiogenic factors’ inhibitors to influence the tumor aberrant vascular proliferation. To inhibit GSC differentiation, this strategy may be combined with other treatments, such as repolarizing macrophage-designed immunotherapeutics [99][92].

3.2. The Perinecrotic or Hypoxic Niche

Hypoxia is one of the main characteristics of glioblastoma. The insufficient blood supply causes hypoxia, leading to pseudo-palisading necrosis. Normal tissular median oxygen saturation is approximately 5%. Instead, in the necrotic regions, the oxygen concentration is less than 2%. This is determined by higher metabolic activity and increased oxygen consumption in the heterogeneous tumor cells [100][93].
Located around the necrotic core, the hypoxic niche is proved to be involved in tumor growth, cell maintenance, stemness induction, and immune surveillance [101][94]. The low oxygen concentration upregulates important proteins, such as hypoxia-inducible factors (HIF1 and HIF2), a dimeric protein complex with an important role in the angiogenesis and dedifferentiation process [55,56,57][52][53][54]. It has been found that many GSCs reside in this niche [62,97,101][59][90][94]. Hypoxia can induce stemness characteristics and determine the increased expression of GSC markers [20,29,33][26][30][95]. GSCs and tumor cells may survive in the hypoxic niche after chemo- and radiotherapy. The cellular death in the necrotic area generates proinflammatory signals, converting inflammatory cells into immunosuppressive cells and inducing angiogenesis [102][96]. Hypoxia can cause the differentiation of GSCs into endothelial cells, promoting the tumor growth from the necrotic area towards the neovascular region [103][97].
Hypoxia plays a pivotal role in the SRC tyrosine kinase pathway. The increase in SRC activity upregulates the VEGF in low-oxygen conditions. Moreover, a correlation between angiogenesis and hypoxia has been proved by the increased vascularization, with integrin upregulation. Additionally, it has been demonstrated that cell survival mechanisms are activated as a result of increased SRC signaling in response to an anti-VEGF agent [104][98]. In addition, the hypoxic conditions increase glycolysis because of the MYC oncoprotein. Its regulation has been linked to the SRC pathway in other tumors [105][99]. Therefore, the SRC–MYC axis may be implicated in metabolic reprogramming also in GBM, apart from the receptor tyrosine kinases’ (RTKs) involvement. The hypoxia-induced SRC pathway results in fostered invasiveness. It consists in integrin β3 and EGFR-vIII interaction, αvβ3 integrin recruitment on cell membranes, and FAK activation, which creates focal adhesion complexes. Furthermore, the EGFRvIII/integrin β3/FAK/SRC axis continues with the intracellular signaling pathway ERK1/2, MAPK, AKT, and STAT3 activation, determining the MMP upregulation, therefore promoting cell invasion [106][100].

3.3. The Invasive Niche

GBM tumor cells can migrate along normal blood vessels, invading normal brain tissue [5]. The deletion of MMP2 and MMP9 boosts the perivascular invasiveness and diminishes angiogenesis [108][101]. The most important cell of the invasive niche is the astrocyte. The close contact between the astrocytes, endothelial cells, and pericytes facilitates the transport of ions and metabolites from the blood vessels to the brain [97][90]. This microenvironment is heterogeneous, and it seems that cell populations within it are plastic. At the cellular level, malignant cells invade diffusely inside the surrounding normal brain parenchyma, followed by increased proliferation of endothelial cells, generating leaky blood vessels and resulting in a hypoxic microenvironment. The invading GBM cells displace the pre-existing astrocytes and pericytes, thereby disrupting the BBB and resulting in leaky blood vessels [109][102]. Paracrine interaction at this level can cause astrocyte proliferation and migration. Among the many receptors expressed by the GSCs, integrin-1 and tropomyosin receptor kinase type A (TRKA) can bind to the connective tissue growth factor (CTGF) released by the astrocytes, and produce zinc finger E-box binding homeobox-1 (ZEB1), leading to tumor cell infiltration [110,111][103][104].
It has been discovered that astrocytes express Sonic hedgehog (SHH), important glioma-associated oncogene (GLI) activator, and stemness promoter [112][105]. Therefore, astrocytes play a key role in GSCs’ preservation and in tumor spreading. Thus, it is expected that large tumors have extensive invasive niches, intense hypoxia, and increased neoangiogenesis.
Funding: This research was funded by Grant PN-III-P4-ID-PCE2020-1649, by the UEFISCDI Authority, Romania.

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