Vascular endothelial growth factor expression in human neuroblastoma: up-regulation by hypoxia

Enhanced angiogenesis apparently contributes to the poor clinical outcome of human neuroblastoma, but the mechanisms have remained unclear. We report here that cultured human neuroblastoma cells express a bioactive endothelial cell growth factor indistinguishable from the angiogenesis stimulator vascular endothelial growth factor (VEGF). VEGF is present in neuroblastoma but not vascular endothelial cells, whereas the corresponding VEGF receptors (Flt-1 and Flk-1/KDR) are expressed in endothelial but not neuroblastoma cells. Exposure of neuroblastoma cells to hypoxia induces a marked increase in bioactive VEGF. VEGF is also present in human neuroblastoma specimens, with substantial amounts in apparently hypoxic neuroblastoma cells, eventually accumulating in tumor microvessels. Our results indicate that VEGF (i) is present in human neuroblastomas, (ii) is up-regulated by tumor hypoxia and (iii) may stimulate neuroblastoma angiogenesis by paracrine mechanisms, thereby contributing to the progression of human neuroblastomas. We suggest that inhibition of VEGF activity may represent a novel approach for the therapy of human neuroblastoma.