VEGFA and neoplasm: Necrosis becomes biologically significant when hypoxia of a layer of cells surrounding the necrotic core of the tumor triggers a cascade of signals mediated by hypoxia-inducible factor-1 (HIF-1) [83] and vascular endothelial growth factor (VEGF) [84], which initiate angiogenesis, i.e. tumor vascularization, by inducing growth and extension of nearby blood vessels.