lesions tended to lose Gfap but gain Nestin positivity and developed the characteristic glioma vasculature and necroses. Thus, sustained overexpression of PDGF-B in astrocytic cells can, on a Tp53 back- ground, lead to uncontrolled expansion of Pdgfr-a+ glial progenitor cells and initiate the development of aggressive GB-like brain tumors. Whereas the PDGF-B overexpressing transgenic mice were phenotypically normal, with survival times that did not differ from WT mice, PDGF-AL-over- expressing mice developed a characteristic, lethal phenotype, after approximately 6 weeks (163). A microscopic analysis of brain tissue showed an increased cellularity due to a highly proliferating, expanding mixed population of astrocytic and OPC-like cells, that spread diffusely throughout the brain and that was also concentrated in distinct brain areas, which overlapped with the areas of transgene activity, including: the roof of the lateral ventricles, in corpus callosum, on the outer surface of the brain, and in the cerebellum. Closely associated with the Gfap+ astrocytic cells were these OPC-like cells with the presence of the oligodendrocyte markers, Pdgfr-a/Olig2/NG2. A few of the PDGF-AL mice presented with very advanced lesions, in the form of a heavy diffuse inﬁl- tration of cells throughout the whole brain, comprising mostly of white matter areas and also in the form of pial outgrowths with excessive masses of mitotic and atyp- ical cells. Also here, the cell population was mixed, with Gfap+ and Pdgfr-a+/Olig2+/NG2+ cells. These lesions were associated with long, angulated and thick-walled capillary structures, strongly positive for Pdgfr-b. Thus, these lesions were found to be similar to human ana- plastic oligoastrocytomas (grade III). The majority of Olig2+/Pdgfr-a+ cells in the exam- ined PDGF-AL brain sections did not express Gfap or the transgene. This observation could be due to the fact that the PDGF-AL transgene produced by NSCs/ astrocytic cells stimulated OPCs in a paracrine fash- ion, or indirectly via changing the cell fate of the NSC/ astrocytic progenitor. Additional experiments are required to resolve this issue. Because PDGF-AL has a C-terminal retention motif that makes it associate with ECM and possibly with the surface of the producing cell, one would expect that its area of action is rather limited. Pdgfr-a is normally expressed by glial progenitor cells (164,165), and as discussed previously PDGF-A is a potent mitogen for OPCs (71,72,74). PDGF-A can also inﬂuence cell fate decisions of cells located in the adult SVZ by inducing them to become OPCs rather than neurons. These cells are sensitive to alterations in the PDGF pathway and can form hyperplasias in response to PDGF-AS, as mentioned previously (76). PDGF and PDGF receptors in glioma 107 In summary, our research work and that of others demonstrate that overexpression of PDGF-AL in astrocytic cells can induce oligoastrocytoma-like lesions at a low rate. Hyperactive production of PDGF-AL in the brain has distinct and strong effects that are different from previously described effects of PDGF-AS and PDGF-B. PDGF-B, in spite of it being expressed in the SVZ by astrocytic cells and carrying the C-terminal retention motif similar to PDGF-AL, resulted in a normal phenotype. It cannot be excluded that the difference was a matter of local concentra- tions of growth factor. However, the fact that con- current loss of p53, a known regulator of stem cell self-renewal resulted in heavy ampliﬁcation of a more undifferentiated Nestin+/mostly Gfap- neural cell type, forming GB-like tumors, suggested a difference in the capacity of progenitors to respond to the PDGF proteins. In conclusion, the role of PDGF-A that was shown in this model system is consistent with the PDGFRA overexpression observed in human low-grade glio- mas, whereas the role of PDGF-B was to promote the full-blown vascular proliferations that are charac- teristic of human GBs. The loss of p53 function may in addition have allowed for enhanced self-renewal of early neural progenitors. SVZ cells are known to be affected by loss of p53 (166). We speculate that in the human situation, the early and almost ubiquitous TP53 mutations/deletions on chromosome 17p observed in low-grade astrocytic glioma may similarly allow for the emergence of stem cell features during glioma progression. Addi- tional experiments are required to resolve this issue. Final comment It has been an honor to participate in the research work on platelet-derived growth factors. It is also stimulating to think of the extensive technical devel- opments and the progress made in the ﬁelds of normal brain development and glioma biology over the last 30 years, and look forward to further developments that may improve the therapy of brain tumor patients. Acknowledgements We acknowledge the ﬁnancial support from the Swedish Cancer Society, the Swedish Childhood Cancer Foundation, the Swedish Research Council, the Cancer Society in Stockholm, and the King Gustaf V Jubilee Fund. We also acknowledge the support from Karolinska Institutet and the Stockholm County Council, to the core facilities Mouse Tissue Analysis (MTA) and Karolinska Healthcare Research Biobank (KHRBB). This review is partly based