Genetic modulation of hypoxia induced gene expression and angiogenesis: relevance to brain tumors.

Angiogenesis is required for the development and biologic progression of infiltrative astrocytomas and takes the form of "microvascular hyperplasia" in glioblastoma multiforme, the most malignant astrocytoma. This pathologic term refers to an abnormal vascular proliferation that is often associated with necrosis and likely originates in hypoxic zones. Both the physiologic response to hypoxia and genetic alterations contribute to this process. The presence of hypoxic regions within an expanding tumor mass leads to upregulation of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), through increased activity of the transcriptional complex HIF-1 (hypoxia-inducible factor-1). HIF-1 mediated gene expression may be directly or indirectly modulated by alterations in oncogenes/tumor suppressor genes that occur during astrocytoma development, including PTEN, TP53, p16(CDKN2A), p14ARF, EGFR, and PDGFR. Genetic alterations are also believed to influence the HIF-independent expression of pro- and anti- angiogenic factors, such as basic fibroblast growth factor (bFGF) and thrombospondin-1 (TSP-1), respectively. Thus, genetic events that occur during the progression of infiltrating astrocytomas promote angiogenesis, both by modulating hypoxia induced gene expression and by regulating of pro- and anti- angiogenic factors.