Restoration of wild-type p16 down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human gliomas

Recent studies have indicated that the loss of p16 is a frequent event in t he progression of malignant gliomas, The loss of p16 promotes the acquisiti on of malignant characteristics in gliomas, which are among the most angiog enic of all human tumors. High-grade gliomas are distinguished from low-gra de gliomas by intense angiogenesis in addition to their frequent loss of p1 6, New therapeutic strategies aimed at inhibiting tumor angiogenesis on the basis of molecular mechanisms are theoretically attractive. Here we evalua te the effect of p16 gene replacement on the angiogenesis of gliomas. Infec tion with a recombinant replication-defective adenovirus vector containing the cDNA of wild-type p16 significantly reduced the expression of vascular endothelial growth factor,which is thought to be a pivotal mediator of tumo r angiogenesis, in p16-deleted glioma cells, Restoring wild-type p16 expres sion into p16-deleted glioma cells markedly inhibited angiogenesis induced by tumor cells in vivo. Furthermore, wild-type p16 inhibited neovasculariza tion more potently than did wild-type p53 transfer. These findings indicate that the p16 gene plays an important role in the regulation of glioma angi ogenesis, suggesting a novel function of the p16 gene.