Abstract
Recent studies have indicated that the loss of p16 is a frequent event in the progression of malignant gliomas. The loss of p16 promotes the acquisition of malignant characteristics in gliomas, which are among the most angiogenic of all human tumors. High-grade gliomas are distinguished from low-grade gliomas by intense angiogenesis in addition to their frequent loss of p16. New therapeutic strategies aimed at inhibiting tumor angiogenesis on the basis of molecular mechanisms are theoretically attractive. Here we evaluate the effect of p16 gene replacement on the angiogenesis of gliomas. Infection 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 tumor angiogenesis, in p16-deleted glioma cells. Restoring wild-type p16 expression into p16-deleted glioma cells markedly inhibited angiogenesis induced by tumor cells in vivo. Furthermore, wild-type p16 inhibited neovascularization more potently than did wild-type p53 transfer. These findings indicate that the p16 gene plays an important role in the regulation of glioma angiogenesis, suggesting a novel function of the p16 gene.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviruses, Human / genetics
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Brain Neoplasms / pathology*
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Cell Cycle / drug effects
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Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis
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Cyclin-Dependent Kinase Inhibitor p16 / deficiency
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Cyclin-Dependent Kinase Inhibitor p16 / physiology*
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / biosynthesis
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Cyclins / genetics
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DNA, Complementary / genetics
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Endothelial Growth Factors / biosynthesis*
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Endothelial Growth Factors / genetics
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Genes, p16*
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Genes, p53
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Genetic Vectors / genetics
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Glioma / pathology*
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Humans
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Lymphokines / biosynthesis*
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Lymphokines / genetics
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Neovascularization, Pathologic / genetics*
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Neovascularization, Pathologic / therapy
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Transfection
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Tumor Suppressor Protein p53 / biosynthesis
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Tumor Suppressor Protein p53 / genetics
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA, Complementary
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Endothelial Growth Factors
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Lymphokines
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Recombinant Fusion Proteins
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Tumor Suppressor Protein p53
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors