PDGFB and P53 in brain tumorigenesis

Abstract

Glioblastoma is the most common, and malignant form of brain tumor. It is characterized by a rapid growth and diffuse spread to surrounding brain tissue. The cell of origin is still not known, but experimental data suggest an origin from a glial precursor or neural stem cell. Analysis of human glioma tissue has revealed many genetic aberrations, among which mutations and loss of TP53 together with amplification and over-expression of PDGFRA are common. Many of the pathways that are found mutated in gliomas, are normally important in regulating stem cell functions.

We have investigated the role of p53 in adult neural stem cells, and found that the p53 protein is expressed in the SVZ in mice. Comparison of neurosphere cultures derived from wt and Trp53-/- mice showed that neural stem cells lacking p53 have an increased self-renewal capacity, proliferate faster and display reduced apoptosis. Gene expression profiling revealed differential expression of many genes, the most prominent being Cdkn1a (p21) which was down-regulated in Trp53-/- neural stem cells.

Mice lacking p53 do not develop gliomas, but the combination of TP53 mutation/deletion together with other genetic aberrations is common in human gliomas of all grades. We generated a transgenic mouse model mimicking human glioblastoma, by over-expressing PDGFB under the GFAP promoter in Trp53-/- mice. The transgene was active in both neural stem cells and astrocytes. These mice developed malignant tumors resembling human glioblastoma at the age of 2-6 months. The tumors showed histopathological features of human glioblastoma, such as pseudopalisading necrosis, microvascular proliferation and pleomorphic nuclei. We used the same transgenic mouse model to study the brain before tumor formation. In the PDGFB/Trp53-/- brain we found increased numbers of Pdgf receptor alpha+ cells and prominent Pdgf receptor beta+ vessels in areas where brain tumor later developed. Neurosphere-forming cells were found in a more widespread location including corpus callosum. Thus, both the neural stem cells and the brain vasculature are affected by the combination of excessive PDGFB and loss of p53.

This investigation provides new insights into the roles of P53 and PDGF in brain tumor formation. We found that loss of p53 leads to deregulation of the stem cell compartment in the mouse SVZ. Expression of PDGFB in the NSCs and astrocytes of Trp53-/- brain, leads to the expansion of cells with neurosphere forming ability to other locations of the brain. As a result of the forced PDGFB expression in Trp53-/- brain, the vasculature is changed and eventually, highgrade gliomas develop.