Genetic and hypoxic regulation of angiogenesis in gliomas

Infiltrative astrocytic neoplasms are by far the most common malignant brain tumors in adults. Clinically, they are highly problematic due to their widely invasive nature which makes a complete resection almost impossible. Biologic progression of these tumors is inevitable and adjuvant therapies are only moderately effective in prolonging survival. Glioblastoma multiforme (GBM; WHO grade IV), the most malignant form of infiltrating astrocytoma, can evolve from a lower grade precursor tumor (secondary GBM) or can present as high grade lesion from the outset, so-called de novo GBM. Molecular genetic investigations suggest that GBMs are comprised of multiple molecular genetic subsets. Notwithstanding the diversity of genetic alterations leading to the GBM phenotype, the vascular changes that evolve in this disease, presumably favoring further growth, are remarkably similar. Underlying genetic alterations in GBM may tilt the balance in favor of an angiogenic phenotype by upregulation of pro-angiogenic factors and down-regulation of angiogenesis inhibitors. Increased vascularity and endothelial cell proliferation in GBMs are also driven by hypoxia-induced expression of pro-angiogenic cytokines, such vascular endothelial growth factor (VEGF). Understanding the contribution of genetic alterations and hypoxia in angiogenic dysregulation in astrocytic neoplasms will lead to the development of better anti-angiogenic therapies for this disease. This review will summarize the properties of angiogenic dysregulation that lead to the highly vascularized nature of these tumors.