Down-regulation of endothelial cell growth inhibitors by enhanced MYCN oncogene expression in human neuroblastoma cells

Recent evidence indicates that the genetic alterations of the multistage pr ocess of malignant transformation appear to activate tumor neovascularizati on by altering the balance between stimulators and inhibitors of angiogenes is. In the present study, we have attempted to define the effect of enhance d MYCN oncogene expression on the profile of endothelial cell growth modula tors in neuroblastoma cells. We report here that conditioned medium of huma n neuroblastoma cells with normal MYCN expression contains three inhibitors of endothelial cell proliferation, which appear to;be novel proteins as ju dged by their physicochemical, immunological and biological properties. All three inhibitors are diminished or become undetectable upon experimental i ncrease of MYCN expression. Our results suggest that enhanced MYCN expressi on in human neuroblastoma cells alters the angiogenic balance by down-regul ating endothelial cell growth inhibitors but leaving the expression of the stimulators unaffected. These data shed light on the molecular mechanisms l inking the genetic changes of malignant transformation with initiation of t umor angiogenesis. Moreover, our observations might explain the poor progno sis of human neuroblastomas following MYCN oncogene amplification through i nitiation of angiogenesis and subsequent tumor growth and spread.