Modeling PDGF-driven gliomagenesis in the mouse

Sammanfattning: Gliomas are the most common form of brain tumors, with glioblastoma being the most aggressive form. Glioblastoma is characterized by a number of genetic aberrations, among them amplification and overexpression of platelet-derived growth factor receptor alpha (PDGFRA) that sometimes occurs together with inactivating mutations or loss of the tumor suppressor p53 (TP53). The infiltrative nature and rapid growth of glioblastoma make it incurable despite extensive treatment. A better understanding of the molecular genetic defects underlying brain tumor development is necessary in order to design novel and more efficient therapies. In the present study we investigated how the combination of increased growth factor signaling and p53 loss induces brain tumors. We generated two transgenic mouse models overexpressing PDGF-B or the long isoform of PDGF-A under the glial fibrillary acidic protein (GFAP) promoter. Thus, the transgene is active in neural stem cells and astrocytes, cells that normally express GFAP. We demonstrate that overexpression of PDGF-B on its own did not trigger brain tumor development. However, when the PDGF-B transgenic mice were crossed onto a Trp53 null background, malignant tumors resembling human glioblastoma appeared at the age of 2-6 months. These tumors displayed histopathological features of human glioblastoma with integrated vascular proliferations expressing PDGFR-β, glial tumor cells expressing PDGFR-α, pseudopalisading necrosis and abnormal cell nuclei. The changes in the brains of PDGF-B/Trp53 null mice were evident long before tumors formed. We found increased numbers of PDGFR-α expressing cells, distorted vasculature, with prominent PDGFR-β expression in areas where brain tumors later occurred. In addition, neurosphere-forming cells were situated in more widespread locations compared to wild type (wt) mice. In contrast to PDGF-B transgenic mice the overexpression of PDGF-AL led to an early lethality of the mice. We detected increased numbers of undifferentiated glial cells and in a few mice neoplastic glioma-like lesions. In summary, these studies provide new insights into the role of excessive PDGF exposure during brain tumor development.