Abstract
Angiogenesis is not restricted to advanced stages of tumor development but is also observed in benign precursor lesions. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis, but the genetic mechanisms controlling its expression in premalignant lesions are poorly described. The Wnt signaling pathway, which is commonly mutated in benign colonic adenomas, was found to strongly up-regulate VEGF. A T-cell factor-4-binding element at -805 bp in the VEGF promoter is an important mediator of this effect. Signaling through the K-ras oncogene, also frequently mutated in benign colonic polyps, up-regulated VEGF in a phosphatidylinositol 3-kinase-dependent manner. Furthermore, K-ras activation appeared to enhance Wnt signaling, which suggests a unique interaction between these two pathways. These studies thus identify VEGF as a novel target of the Wnt pathway in early colonic neoplasia and serve to underscore the importance of angiogenesis in premalignant disease.
MeSH terms
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Androstadienes / pharmacology
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Colonic Neoplasms / blood supply
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism*
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Endothelial Growth Factors / biosynthesis*
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Endothelial Growth Factors / genetics
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Neoplastic / genetics
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Gene Expression Regulation, Neoplastic / physiology*
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Genes, Regulator
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Genes, ras / genetics
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Genes, ras / physiology*
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HeLa Cells
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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 / metabolism
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Phosphatidylinositol 3-Kinases / physiology
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Phosphoinositide-3 Kinase Inhibitors
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Precancerous Conditions / blood supply
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Precancerous Conditions / genetics
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Precancerous Conditions / metabolism*
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Promoter Regions, Genetic
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins p21(ras) / genetics
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Proto-Oncogene Proteins p21(ras) / physiology
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Signal Transduction / physiology
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Transfection
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Tumor Cells, Cultured
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Up-Regulation / genetics
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Wnt Proteins
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Wortmannin
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Zebrafish Proteins*
Substances
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Androstadienes
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Endothelial Growth Factors
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Enzyme Inhibitors
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Lymphokines
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Wnt Proteins
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Zebrafish Proteins
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HRAS protein, human
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Proto-Oncogene Proteins p21(ras)
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Wortmannin