106 I. Nazarenko et al. NSC NSC NSC PC PC CSC DC De-differentiation Figure 2. Three possible ways for a cancer stem cell (CSC) to arise: a neural stem cell (NCS) acquires a mutation; a progenitor cell (PC) acquires two or more mutations; or a fully differentiated cell (DC) undergoes several mutations that transform and drive it back to a stem- like state. PDGF-B-induced tumor incidence and progression (157). In order to test the tumorigenic potential of adult glial progenitors, PDGF-B was retrovirally expressed in rat corpus callosum, leading to transformation of NG2-positive OPCs and development of GBs (158). Injection of retroviral PDGF-B in newborn rats causes a shift in the differentiation fate of the NSCs, generating more pdgfr-a/NG2/Olig2- expressing OPCs that do not differentiate into mature oligodendrocytes (159). Moreover, excessive expression of PDGF-B in neural progenitor cells forced their respeciﬁcation towards the oligoden- droglial lineage with development of highly malig- nant oligodendroglial tumors in mice (160,161). Different capacities of PDGF-B and PDGF-AL in brain tumor development To investigate the roles of PDGF-B and PDGF-A in brain tumor development, two transgenic mouse models were generated in which overexpression of human PDGF-B (162) and PDGF-AL (163), respec- tively, was induced in astrocytic cells of the brain by a human GFAP promoter fragment. Both these PDGF proteins have the C-terminal motif, attaching them to the ECM, but while PDGF-B binds to both a- and b-receptors, PDGF-AL binds only to the a-receptor. The GFAP promoter fragment used is active during embryogenesis, in radial glial cells of the telenceph- alon and in the cerebellar anlage, and stays active postnatally in astrocytic cells, including activity in astrocytic cells of the adult SVZ. The effects of PDGF-AL and PDGF-B were found to be different. The PDGF-B-overexpressing transgenic mice did not develop brain tumors, and the mice were pheno- typically normal. They were therefore crossed with Trp53 mice to obtain PDGF-B/p53-null off- spring. In this way, two aberrations commonly pres- ent together in human gliomas could be combined. On the Tp53 background, two PDGF-B trans- genic mouse lines developed brain tumors at high rates, 68 and 43%, and tumors occurred between 2 and 6 months after birth. They spread diffusely throughout the brain tissue and displayed microvas- cular proliferations as well as necroses lined by pali- sading cells. Thus, morphologically the tumors had the characteristics of human GB. According to pre- vious ﬁndings from human brain tumors, PDGFR-a is localized on glial tumor cells, and PDGFR-b on the vasculature (35). This was also the case in the PDGF- B/p53-null tumors that were generated. The majority of glioma cells proper, but not the tumor vasculature, expressed the transgene, and together this indicated the possibility of both autocrine and paracrine stim- ulatory loops similar to those in human tumors (162). Small Gfap+/Nestin+ SVZ lesions were present in the lateral ventricular wall and were suggested to repre- sent a point of origin. Due to the variable location of the tumors and the fact that the PDGF-B transgene was produced by astrocytic cells throughout the brain, such as in the glia limitans, and not only in the SVZ, another suggested possibility was that astrocytes dedi- fferentiated and transformed into tumor cells. Larger