104 I. Nazarenko et al. downstream pathways supporting cellular growth (through mTOR) and proliferation (through inhibi- tion of GSK3-b) (94). Loss of cell cycle regulation in glioma The tumor suppressor protein p53 is a major regulator of multiple cellular responses, including those induced by DNA damage, oncogene activation, and hypoxia (95). In GBs, TP53 is found to be mutated in 35% of all cases (82). It has been described that somatic TP53 mutations are more common in low-grade astrocyto- mas and secondary GBs than in primary GBs and that the spectrum of mutations is different (79,96). How- ever, recent studies have conﬁrmed that TP53 muta- tions are also prevalent in primary GBs (97,98). In addition, chromosome 17p is an early and frequent target for LOH in both low-grade and high-grade gliomas (99,100). Inactivation of p53 can also occur through other mechanisms such as viral infection, loss of ARF, or overexpression of MDM2 (101). The progression from G1 to S phase in the cell cycle is controlled by the p16INK4A/CDK4/RB1 pathway. Genetic alterations involving this pathway are found in 78% of glioblastomas (82). Molecular-genetic subclassiﬁcation of high-grade glioma Previous clinical and genetic studies of GBs described two subtypes, primary and secondary. However, recent genomic studies have provided more detailed information about the molecular mechanisms involved in glioma initiation and progression and have identiﬁed new subgroups based on glioma mole- cular signatures (82,97,102-104) that are described as classical, mesenchymal, proneural, and neural sub- types. Among these subtypes, the proneural subtype is characterized by PDGFRA ampliﬁcation and loss or mutation of TP53, CDKN2A, and PTEN. Mutation of the isocitrate dehydrogenase 1 gene (IDH-1) (see below) and activation of PI3K and PDGFR-a path- ways are also frequent characteristics of this subtype. GBs of the secondary subtype have gene expression proﬁles corresponding to those of neuronal (SOX2, DCX, etc.) and oligodendrocytic (PDGFRA, OLIG2, etc.) progenitor cells. These ﬁndings have been com- prehensively discussed (90,105,106). In addition to distinct genomic proﬁles, the classical, mesenchymal, and proneural subtypes vary in their biological behavior and response to adjuvant treatments (107). Recent results from GB tumor DNA sequencing studies also revealed previously unknown important genetic changes. Spontaneous mutations of IDH-1 and IDH-2 appeared as strong prognostic indicators in anaplastic astrocytoma and secondary GB. In patients with secondary GB, mutation of IDH-1 is linked to a median survival of 31 months compared to 15 months for the group of patients with wild-type (WT) IDH-1 (104). Importantly, these mutations also occur together with TP53 mutations in lower- grade tumors. Neural stem cells A common belief of classical neuroscience was that once development was completed, no new neurons were produced. However, this view has changed, and in the 1960s the ﬁrst evidence of adult neuro- genesis appeared from studies in rat brain (108). During brain development, neuroepithelial stem cells situated in the ventricular zone of the lateral ventricle wall give rise to neurons and glia. Even though it was thought that neurogenesis is mostly completed by birth, it continues throughout life. Cells, commonly known as neural stem cells (NSCs), have a capacity to self-renew and differen- tiate along multiple lineages, contributing to tissue maintenance and regeneration in case of injury in the adult CNS (109,110). There are two brain areas in mice where adult NSCs are known to reside, the SVZ of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. The largest source of NSCs in the adult mammalian brain is the SVZ, which is described as a thin layer of proliferative cells in the lateral wall of the lateral ventricle (109,111-113). Adult NSCs are not unstructured undifferentiated cells; they show features of differen- tiated astrocytes and express glial ﬁbrillary acidic protein (Gfap). This subpopulation of Gfap+ cells in the SVZ (B cells) produces a transit-amplifying cell population (C cells) that then gives rise to migratory neuroblasts (A cells) and OPCs. It has been shown that adult NSCs are derived from radial glia, the stem cells of the developing brain, which in turn are derived from the neuroepithelium (114). In addition to Gfap, NSCs are characterized by expression of Nestin (112). Sox2 is also found in NSCs of the SVZ (115) and SGZ (116) and is required to maintain the immature state of NSCs and to preserve their capa- city to proliferate and generate neurons (117,118). There are several architectural elements contribut- ing to adult neurogenesis, such as localization of NSCs near the cerebrospinal ﬂuid, close association with blood vessels, a rich extracellular matrix (ECM), specialized basal lamina, and widespread cell-to-cell interactions (119,120). The endothelial cells of blood vessels release factors that promote the self-renewal of NSCs (121,122).