Glial Progenitors in Adult White Matter Are Driven to Form Malignant Gliomas by Platelet-Derived Growth Factor-Expressing Retroviruses

Abstract

To test the gliomagenic potential of adult glial progenitors, we infected adult rat white matter with a retrovirus that expresses high levels of PDGF and green fluorescent protein (GFP). Tumors that closely resembled human glioblastomas formed in 100% of the animals by 14 d postinfection. Surprisingly, the tumors were composed of a heterogeneous population of cells, <20% of which expressed the retroviral reporter gene (GFP). The vast majority of both GFP+ and GFP- tumor cells expressed markers of glial progenitors. Thus, the tumors arose from the massive expansion of both infected and uninfected glial progenitors, suggesting that PDGF was driving tumor formation via autocrine and paracrine stimulation of glial progenitor cells. To explore this possibility further, we coinjected a retrovirus expressing PDGF-IRES-DsRed with a control retrovirus expressing only GFP. The resulting tumors contained a mixture of red cells (PDGF-expressing/tumor-initiating cells) and green cells (recruited progenitors). Both populations were highly proliferative and infiltrative. In contrast, when the control GFP retrovirus was injected alone, the animals never formed tumors and the majority of infected cells differentiated along the oligodendrocyte lineage. Together, these results reveal that adult white matter progenitors not only have the capacity to give rise to gliomas, but resident progenitors are recruited to proliferate within the mitogenic environment of the tumor and in this way contribute significantly to the heterogeneous mass of cells that compose a malignant glioma.