Regulatory pathways in neural stem cells and their relation to brain tumors It was demonstrated that a fraction of SVZ stem cells express PDGFR-a (76) and that EGFR is expressed in type B and type C cells (123). It has also been shown that NSCs proliferate in response to both PDGF and EGF in vitro (110,112,124,125), and EGF is used in cultures to keep NSCs in an undif- ferentiated state (110). Infusion of EGF into the brain results in a signiﬁcant ampliﬁcation of endogenous SVZ precursor cells (123,124,126) and promotes oligodendrogenesis (127). When active EGF receptor was introduced into Ink4a/Arf-deﬁcient mice, it caused dedifferentiation of astrocytes, and high-grade gliomas developed from both dedifferentiated astro- cytes and NSCs carrying the same genetic alteration (128). PDGF also has a dedifferentiating effect on mouse astrocytes (129), and infusion of PDGF-A into the lateral ventricle of adult mouse brain can induce the proliferation of PDGFR-a–positive NSCs that may form glioma-like lesions (76). The tumor suppressor p53 plays an important role during development of the CNS by inducing apo- ptosis of neurons and neural progenitors to adjust the cell number (130), and a subset of Trp53-deﬁcient mice develop exencephaly (131,132). P53 is present in the adult mouse lateral ventricle wall SVZ and regulates NSCs proliferation, apoptosis, and self- renewal. Gene expression proﬁling identiﬁed several genes that were down-regulated in Trp53 NSCs in vitro, such as the cell cycle regulatory factors p21 and p27 (133). Cancer stem cells; heterogeneity of glioma cells The heterogeneity of glioblastoma cells has become increasingly appreciated as a signiﬁcant factor, allow- ing for paracrine stimulatory mechanisms in tumors (134). It has also been shown that within some tumors there is a subset of cancer cells (CSCs) with stem cell- like features: unlimited self-renewal, multipotency, and tumor-initiating capacity in vivo. These cells may give rise to a number of new cell types in the tumor and maintain the neoplastic growth over time. CSCs have been described in brain tumors (135-140). A high rate of recurrence and resistance to treat- ment are major characteristics of malignant gliomas. It has been reported that brain CSCs have the capacity to survive treatment and give rise to a new tumor with characteristics of the original tumor (141). Since the adult brain has only a limited population of prolifer- ating cells that are able to accumulate the several mutations required for transformation into a cancer cell, the adult NSCs/progenitor cells have been PDGF and PDGF receptors in glioma 105 suggested as candidate sources for brain CSCs (Figure 2). In addition, it has been suggested that tumorigenic events can lead to dedifferentiation of a mature cell and thereby gain of stem cell properties (Figure 2) (128,129,142). NSCs are relatively quies- cent cells, whereas glioblastoma cells are highly pro- liferative. It is therefore possible that the majority of tumor cells represent rapidly amplifying progenitors rather than stem cells. Similar to NSCs, brain CSCs are located in a special microenvironment. They are found in close proximity to blood vessels, often in hypoxic areas (143). They have been shown to stimulate angiogen- esis by secreting VEGF (144), and in return they receive a constant supply of nutrients and oxygen (145). Glioma cells migrate along the tumor vessels into the surrounding tissue. Other components of the perivascular niche, such as adhesion to the surround- ing cells or ECM are important for CSCs main- tenance. L1CAM, a cell surface molecule that intervenes in cell–ECM and cell-to-cell interactions, was found to be highly expressed in glioma CSCs (146,147). PDGF-driven glioma models To address the functional role of PDGF in brain tumors, several experimental models have been cre- ated to induce gliomas, mostly in mice by forced expression of PDGF. In general, overexpression of PDGF in the brain leads to excessive production of OPCs and, if in a permissive setting, results in mainly oligodendroglioma-like tumors. The ﬁrst attempt to model ‘PDGF-induced’ glioma was made by Deinhardt (148), who injected SSV, with the v-sis oncogene, into the brains of newborn marmosets. This resulted in gliomas, morphologically indistinguishable from human tumors, described in a review by Nistér and Westermark (149). Many years later, when a PDGF-B-encoding retrovirus was used for injection in newborn mice, highly malignant brain tumors developed in 40% of all animals, and further in vitro experiments showed that autocrine PDGF stimulation was an important step in their generation (150,151). As an alternative approach, the RCAS/TV-A model system was developed for brain tumor studies (152,153) and has been successfully used to assess the signiﬁcance of PDGF and downstream signaling mechanisms in glioma. Tumor progression can be enhanced in the PDGF-induced glioma models by combination of another genetic aberration such as loss of Ink4a/Arf, Trp53, or Pten (154-156). However, a disruption of the homology-directed DNA repair mechanism, by introduction of RAD51, decreases