PDGFB and P53 in brain tumorigenesis

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

Novel Perspectives on p53 Function in Neural Stem Cells and Brain Tumors

Malignant glioma is the most common brain tumor in adults and is associated with a very poor prognosis. Mutations in the p53 tumor suppressor gene are frequently detected in gliomas. p53 is well-known for its ability to induce cell cycle arrest, apoptosis, senescence, or differentiation following cellular stress. That the guardian of the genome also controls stem cell self-renewal and suppresses pluripotency adds a novel level of complexity to p53. Exactly how p53 works in order to prevent malignant transformation of cells in the central nervous system remains unclear, and despite being one of the most studied proteins, there is a need to acquire further knowledge about p53 in neural stem cells. Importantly, the characterization of glioma cells with stem-like properties, also known as brain tumor stem cells, has opened up for the development of novel targeted therapies. Here, we give an overview of what is currently known about p53 in brain tumors and neural stem cells. Specifically, we review the literature regarding transformation of adult neural stem cells and, we discuss how the loss of p53 and deregulation of growth factor signaling pathways, such as increased PDGF signaling, lead to brain tumor development. Reactivation of p53 in brain tumor stem cell populations in combination with current treatments for glioma should be further explored and may become a viable future therapeutic approach

PDGF and PDGF receptors in glioma

The family of platelet-derived growth factors (PDGFs) plays a number of critical roles in normal embryonic development, cellular differentiation, and response to tissue damage. Not surprisingly, as it is a multi-faceted regulatory system, numerous pathological conditions are associated with aberrant activity of the PDGFs and their receptors. As we and others have shown, human gliomas, especially glioblastoma, express all PDGF ligands and both the two cell surface receptors, PDGFR-α and -β. The cellular distribution of these proteins in tumors indicates that glial tumor cells are stimulated via PDGF/PDGFR-α autocrine and paracrine loops, while tumor vessels are stimulated via the PDGFR-β. Here we summarize the initial discoveries on the role of PDGF and PDGF receptors in gliomas and provide a brief overview of what is known in this field

What underlies the diversity of brain tumors?

Glioma and medulloblastoma represent the most commonly occurring malignant brain tumors in adults and in children, respectively. Recent genomic and transcriptional approaches present a complex group of diseases and delineate a number of molecular subgroups within tumors that share a common histopathology. Differences in cells of origin, regional niches, developmental timing, and genetic events all contribute to this heterogeneity. In an attempt to recapitulate the diversity of brain tumors, an increasing array of genetically engineered mouse models (GEMMs) has been developed. These models often utilize promoters and genetic drivers from normal brain development and can provide insight into specific cells from which these tumors originate. GEMMs show promise in both developmental biology and developmental therapeutics. This review describes numerous murine brain tumor models in the context of normal brain development and the potential for these animals to impact brain tumor research

GFAP promoter driven transgenic expression of PDGFB in the mouse brain leads to glioblastoma in a Trp53 null background

Glioblastomas are the most common and malignant astrocytic brain tumors in human adults. The tumor suppressor gene TP53 is commonly mutated and/or lost in astrocytic brain tumors and the TP53 alterations are often found in combination with excessive growth factor signaling via PDGF/PDGFRalpha. Here, we have generated transgenic mice over-expressing human PDGFB in brain, under control of the human GFAP promoter. These mice showed no phenotype, but on a Trp53 null background a majority of them developed brain tumors. This occurred at 2-6 months of age and tumors displayed human glioblastoma-like features with integrated development of Pdgfralpha+ tumor cells and Pdgfrbeta+/Nestin+ vasculature. The transgene was expressed in subependymal astrocytic cells, in glia limitans, and in astrocytes throughout the brain substance, and subsequently, microscopic tumor lesions were initiated equally in all these areas. With tumor size, there was an increase in Nestin positivity and variability in lineage markers. These results indicate an unexpected plasticity of all astrocytic cells in the adult brain, not only of SVZ cells. The results also indicate a contribution of widely distributed Pdgfralpha+ precursor cells in the tumorigenic proces

What underlies the diversity of brain tumors?

Glioma and medulloblastoma represent the most commonly occurring malignant brain tumors in adults and in children respectively. Recent genomic and transcriptional approaches present a complex group of diseases, and delineate a number of molecular subgroups within tumors that share a common histopathology. Differences in cells of origin, regional niches, developmental timing and genetic events all contribute to this heterogeneity. In an attempt to recapitulate the diversity of brain tumors, an increasing array of genetically engineered mouse models (GEMMs) has been developed. These models often utilize promoters and genetic drivers from normal brain development, and can provide insight into specific cells from which these tumors originate. GEMMs show promise in both developmental biology and developmental therapeutics. This review describes numerous murine brain tumor models in the context of normal brain development, and the potential for these animals to impact brain tumor research