Glioma Stem Cells and Their Microenvironments: Providers of Challenging Therapeutic Targets

Table 1

Key molecules involved in normal neural stem cells and in glioma cancer stem cells.

Name	Roles/involvement	Reference(s)
Receptors
Notch-1	Notch signaling enhances NSC survival, proliferation, and self-renewal during embryonic CNS development.	[43]
Notch-2	Primary GSCs have high Notch-2 expression. Constitutive Notch-2 signaling in neural stem cells generates similar features to GSCs. Notch signaling represents a pathway common in the midst of regulating the GSC phenotype.	[44, 45]
PTCH1; (protein patched homologue 1)	Proliferation of NSC and GSC.; PTCH highly expressed in astrocytoma, oligodendroglioma, and GBM.	[46]
PROM1/CD133; (prominin-1)	Maintenance of stem-cell properties (differentiation suppressor) lost during CSC differentiation, different glycosylation pattern in CSC.	[22]
CXCR4	Stimulates proliferation and promotes GSC-mediated angiogenesis.	[47]
EGFR; (epidermal growth factor receptor)	Often amplified and mutated in high-grade gliomas.; Increases proliferation and tumorigenicity, inhibits apoptosis, regulates angiogenesis and stemness, and mediates resistance to oxidative stress and ionizing radiation.	[48, 49]
IL-6R	Promotes self-renewal, GSC maintenance, and tumorigenicity and suppresses apoptosis.	[50]
Integrin 6	Promotes self-renewal, proliferation, tumorigenicity, and GSC marker.	[25]
PDGFRA; (platelet-derived growth factor receptor-alpha protein)	Conversion of oligodendrocyte progenitors into neural stem-like cells.; Expressed in gliomas.; Amplified and mutated in glioblastoma.	[51]
Ligands
BMPs; (bone morphogenetic proteins)	Reduce proliferation and abolish tumorigenicity.; Induce differentiation, determined by an increase in the number of glial fibrillary acidic protein- (GFAP-) positive cells and delay tumor growth.	[52, 53]
SHH; (sonic hedgehog protein)	In GSCs, Hedgehog-Gli signaling increases expression of stem genes (e.g., CD133, Olig2, Oct4, Nanog, and Sox2), promotes self-renewal, and supports glioma growth and survival.; Proliferation of NSC and GSC.; Activation of SHH pathway in brainstem glioma.	[54–57]
TGF	Promotes self-renewal, tumorigenicity, proliferation, and invasion and maintains stemness in GSCs.	[58, 59]
WNT	Regulates GSCs maintenance, proliferation, and tumorigenicity, inhibits apoptosis and differentiation, and regulates cell migration.	[60]
Transcription factors and chromatin-modifying proteins
Bmi1; (polycomb complex protein)	Found in undifferentiated NSCs and high grade gliomas, with higher expression correlating to poor glioma patient survival.; Found enriched in GSCs and required for their self-renewal.	[61, 62]
Oct4	Oct4 is highly expressed in human gliomas and correlates with tumor grade, promotes colony formation, and inhibits differentiation in glioma cells, potentially through upregulation of phosphorylated STAT3.	[59]
Sox2	Oct4 and Sox2 are increased in GSCs and promote tumorigenic activity as validated by tumor sphere formation and intracerebral tumor formation.	[29, 32]
Nanog	Nanog expression is higher in GSCs, coexpressed with CD133+ glioma cells and less expressed in regions enriched for the differentiation marker, GFAP.; Interacts with the Hedgehog-Gli pathway to modulate GSC proliferation, neurosphere formation, and tumor promotion in orthotopic xenografts.	[31, 63]
c-Myc	c-Myc levels correlate with glioma tumor grade and are highly expressed in GSCs relative to non-GSCs. Not only does c-Myc promote proliferation, but it may also represent a GSC-specific survival factor.; c-Myc is highly expressed in approximately half of CD133+ cells acutely isolated from primary human GBM specimens, whereas c-Myc expression is considerably lower in the CD133− fraction.	[64, 65]
Olig2	Highly expressed in diffuse gliomas including astrocytomas, oligodendrogliomas, and oligoastrocytomas.; Controls GSC proliferation, cell adhesion, and cell cycle progression.	[66, 67]
STAT3	Promotes proliferation, stemness, self-renewal, tumorigenicity, immunosuppression, induction of Tregs, and TAMs and inhibits apoptosis.	[68–70]
Musashi; (RNA-binding protein Musashi homolog 1)	Protein alteration favors tumorigenesis.; NSC and HSC display Musashi alteration. Consistently correlated with the tumor proliferation in gliomas.; Expressed in GSCs and in neurospheres derived from brain tumors, being correlated with tumor grade and proliferation rate.	[71]
GLI1, GLI2, and GLI3	GLI1 protein expressed in NSC.; Originally isolated from glioblastoma.; GLI expressed in GBM, astrocytoma, and oligodendroglioma.	[46]
miRNAs underexpressed
miR-7	Inhibits GSCs proliferation and invasion.	[72]
miR-124 and miR-137	Decrease proliferation and increase differentiation of GSCs; G1 arrest.	[73, 74]
miR-34a	Inhibition of invasion, proliferation, and cell cycle progression; inhibition of Notch-1, Notch-2, and c-Met.	[75]
miR-451 and miR-452	Decrease proliferation and viability.	[76]
miR-101	Decreases invasion, proliferation, and angiogenesis.	[77]
miR-218	Decreases migration, proliferation, and self-renewal.	[78]
miR-451	Decreases proliferation and viability and inhibits self-renewal.	[79]
miRNAs overexpressed
miR-21	Increases proliferation and invasion and decreases apoptosis and chemoresistance.	[72, 80, 81]
miR-10b	Increases invasiveness.	[82]
miR-17-92 cluster	Increases tumorigenesis and cell cycle progression.	[83]
miR-93	Increases tumor growth and angiogenesis.	[84]
miR-125b	Decreases apoptosis.	[85, 86]
miR-196a	Decreases patient survival.	[87]
Enzyme
IDH1/IDH2 (isocitrate dehydrogenase 1/2)	Catalyses neomorphic formation of 2-hydroxyglutarate.; Frequent in astrocytomas, oligodendrogliomas, and glioblastomas.	[88]
Intermediate filament
Nestin	Frequently expressed in high grade gliomas, especially in primary tumors in patients with dissemination, being a predictive marker for poor survival rate.; Positive coexpression for Nestin/CD133 is an indicator of poor prognosis.	[28, 89]