due to severe hypomyelination (71,72). Finally, the amount of PDGF-A available controls the number of OPCs not only during embryogenesis, but also in the adult brain (73,74). Recent in vitro experiments demonstrated the abil- ity of PDGF-A to induce embryonic Nestin+ neural progenitor cells towards becoming NG2+ oligoden- drocyte precursors (75). In addition, direct stimula- tion with PDGF-A of cells in the adult lateral ventricular wall subventricular zone (SVZ), induces PDGFR-a–positive neural stem cells (NSCs) to give rise to oligodendrocyte lineage cells, but not neuronal lineage cells (76,77). Human glioma tumors Gliomas are the most common primary tumors of the CNS mainly affecting adults. They are categorized into astrocytomas, oligodendrogliomas, oligoastrocy- tomas, and ependymomas, reﬂecting their histologic appearance. In a clinical setting, the malignancy grade of the tumor is an essential factor to help predict the outcome of the patient and the choice of therapy. According to the World Health Organization (WHO) grading scale for tumors of the nervous system, lesions with no atypia/low proliferative activities are denoted as grade I, quite often curable upon surgical removal. Once the lesion is inﬁltrative it is designated as grade II, and tumors of this grade can progress to higher grades. Grade III are lesions with accelerated mitotic activity and nuclear atypia/anaplasia. Grade IV is the most malignant tumor grade with a fatal outcome. Grade IV tumors often present with inﬁltration into surrounding tissue, high mitotic activity, characteris- tic necrotic areas, and extensive microvascular pro- liferations (78). Diffuse astrocytomas grade II and III may prog- ress to grade IV, which is then referred to as sec- ondary glioblastoma (GB). However, the majority of GB tumors develop de novo, with no previous his- tory, and are referred to as primary glioblastomas (78). The primary and secondary GBs exhibit the same histopathologic characteristics, even though they differ in both genetic changes and clinical history (79). Activated growth factor pathways in glioma A frequent hallmark of malignant gliomas is activation of RTK signaling pathways, most commonly caused by EGFR mutation/ampliﬁcation or PDGFR ampli- ﬁcation/overexpression. EGF/TGF-a and PDGF proteins exert their activity by binding to and activat- ing cell surface tyrosine kinase receptors, which leads to receptor dimerization, transphosphorylation, and PDGF and PDGF receptors in glioma 103 subsequent activation of intracellular signaling path- ways, such as PI3K/AKT and RAS/MAPK. Ampliﬁcation of EGFR is found in about 43% of primary GBs and is associated with EGFR overex- pression. However, EGFR overexpression has rarely been found in secondary GBs (79-83). Furthermore, 70%–90% of all GBs with EGFR overexpression have rearrangements of the gene (82). The most wide- spread mutated variant of EGFR is EGFRvIII, which contains a 267-bp deletion of exons 2–7 in the extra- cellular domain, resulting in ligand-independent acti- vation of the receptor (79,83-85). Overexpression/hyperactivity of PDGF ligands and receptors are frequent events in human gliomas of all grades (33,35,86,87), and their expression pattern in tumors suggests the presence of autocrine and para- crine stimulatory loops (36,40). Ampliﬁcation of PDGF and PDGFR genes is not as common as the ampliﬁcation of EGFR (36,39) and occurs only in 11% of GBs. However, this still makes PDGFRA the second most frequently ampliﬁed RTK gene in these tumors (82). Activating rearrangements of PDGFRA in GBs is very rare. Previously, only two reports described an in-frame deletion of the Ig-like domain, the PDGFRAD8,9 mutant and a mutation in the C-terminal of PDGFRA (88,89). Recent sequencing analysis of GBs has identiﬁed several point mutations in the Ig-like domains (90), and another study dis- covered a gene fusion between PDGFRA and the kinase insert domain receptor (KDR/VEGFR2) gene (91). Ozawa and colleagues have also demon- strated that the previously discovered PDGFRAD8,9 mutant is present in 40% of GBs with PDGFRA ampliﬁcation. Alterations in other RTK genes have been reported, including ERBB2/HER2 mutations and MET ampli- ﬁcations in 8 and 4% of GBs analyzed, respectively (82). High levels of active RAS have been reported in high-grade astrocytomas, but unlike in many cancers mutated RAS is rarely present in malignant gliomas (2%) (82). Neuroﬁbromin-1 (NF1) is a tumor sup- pressor and a negative regulator of RAS. Mutations of NF1 have been linked to the hereditary condition neuroﬁbromatosis type-1, where patients are predis- posed to glioma development (92). NF1 was recently found to be mutated in 18% of glioblastomas (82). Activation of PI3K/AKT signaling can be achieved by loss of the tumor suppressor gene PTEN or by mutations in PIK3CA. PTEN is a direct antagonist of the activity of PI3K. PTEN loss is rare in low- grade gliomas, but mutations and deletions are found in 50% of high-grade gliomas (93) and are associated with poor patient survival. As a result, inactive PTEN leads to AKT hyperactivation, which in turn triggers