PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo

We present evidence that some low-grade oligodendrogliomas may be comprised of proliferating glial progenitor cells that are blocked in their ability to differentiate, whereas malignant gliomas have additionally acquired othe r mutations such as disruption of cell cycle arrest pathways by loss of Ink 4a-Arf. We have modeled these effects in cell culture and in mice by genera ting autocrine stimulation of glia through the platelet-derived growth fact or receptor (PDGFR). In cell culture, PDGF signaling induces proliferation of glial precursors and blocks their differentiation into oligodendrocytes and astrocytes. In addition, coexpression of PDGF and PDGF receptors has be en demonstrated in human gliomas, implying that autocrine stimulation may b e involved in glioma formation. In this study, using somatic cell type-spec ific gene transfer we investigated the functions of PDGF autocrine signalin g in gliomagenesis by transferring the overexpression of PDGF-beta into eit her nestin-expressing neural progenitors or glial fibrillary acidic protein (GFAP)-expressing astrocytes both in cell culture and in vivo. In cultured astrocytes, overexpression of PDGF-beta caused significant increase in pro liferation rate of both astrocytes and neural progenitors. Furthermore, PDG F gene transfer converted cultured astrocytes into cells with morphologic a nd gene expression characteristics of glial precursors. In vivo, gene trans fer of PDGF to neural progenitors induced the formation of oligodendrogliom as in about 60% of mice by 12 wk of age; PDGF transfer to astrocytes induce d the formation of either oligodendrogliomas or mixed oligoastrocytomas in about 40% of mice in the same time period. Loss of Ink4a-Arf, a mutation fr equently found in high-grade human gliomas, resulted in shortened latency a nd enhanced malignancy of gliomas. The highest percentage of PDGF-induced m alignant gliomas arose from of Ink4a-Arf null progenitor cells. These data suggest that chronic autocrine PDGF signaling can promote a proliferating p opulation of glial precursors and is potentially sufficient to induce gliom agenesis. Loss of Ink4a-Arf is not required for PDGF-induced glioma formati on but promotes tumor progression toward a more malignant phenotype.