| Research Abstract |
In addition to the alteration of p16, p53, and PTEN, the malignant progression from low to high-grade gliomas is accompanied by overproduction of angiogenic factors and suppression of anti-angiogenic effectors. However, the relationship between tumor suppressor genes and angiogenic-related substances in human gliomas has not been sufficiently resolved. The aim of the present study was to investigate the effects of p16, p53, and PTEN gene transfer on glioma angiogenesis. We focused on vascular endothelial growth factor (VEGF) as a potent angiogenic stimulator, and thrombospondin-1 (TSP-1) and TSP-2 as angiogenic inhibitors. The p16 gene is endogenously deleted in U251MG and U87MG. The p53 gene is mutated in U251MG but is intact in U87MG cells. Endogeneous PTEN is mutated in both U251MG and U87MG. Infection with recombinant replication-defective adenovirus vector containing the cDNA of wild-type p16, p53, or PTEN significantly reduced the expression of VEGF depending on the gene status of each glioma cell line. TSP-1 and TSP-2 expression was enhanced by the transduction of wild-type p53 or PTEN. In contrast, the restoration of wild-type p16 had no effect on TSP-1 expression, but increased TSP-2 in p16-deleted glioma cells. In vivo angiogenesis assay showed that adenovirus-mediated gene transfer of p16, p53, and PTEN markedly inhibited tumor neovascularization. In conclusion, these suppressor genes, which are frequently observed to lose function in human gliomas, are also closely related to tumor angiogenesis. The present study suggests that p16, p53, and PTEN gene transfer may be a suitable anti-angiogenic therapy for malignant gliomas.
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