Institutionen för onkologi-patologi / Department of Oncology-Pathology
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