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

Enhanced angiogenesis apparently contributes to the poor clinical outcome o f human neuroblastoma, but the mechanisms have remained unclear. We report here that cultured human neuroblastoma cells express a bioactive endothelia l cell growth factor indistinguishable from the angiogenesis stimulator vas cular endothelial growth factor (VEGF). VEGF is present in neuroblastoma bu t not vascular endothelial cells, whereas the corresponding VEGF receptors (Flt-1 and Flk-1/ KDR) are expressed in endothelial but not neuroblastoma c ells. Exposure of neuroblastoma cells to hypoxia induces a marked increase in bioactive VEGF. VEGF is also present in human neuroblastoma specimens, w ith substantial amounts in apparently hypoxic neuroblastoma cells, eventual ly accumulating in tumor microvessels. Our results indicate that VEGF (i) i s present in human neuroblastomas, (ii) is up-regulated by tumor hypoxia an d (iii) may stimulate neuroblastoma angiogenesis by paracrine mechanisms, t hereby contributing to the progression of human neuroblastomas. We suggest that inhibition of VEGF activity may represent a novel approach for the the rapy of human neuroblastoma. (C) 1999 Wiley-Liss, Inc.