Abstract
The switch from a quiescent tumor to an invasive tumor is accompanied by the acquisition of angiogenic properties. This phenotypic change likely requires a change in the balance of angiogenic stimulators and angiogenic inhibitors. The nature of the angiogenic switch is not known. Here, we show that introduction of activated H-ras into immortalized endothelial cells is capable of activating the angiogenic switch. Angiogenic switching is accompanied by up-regulation of vascular endothelial growth factor and matrix metalloproteinase (MMP) bioactivity and downregulation of tissue inhibitor of MMP. Furthermore, we show that inhibition of phosphatidylinositol-3-kinase leads to partial inhibition of tumor angiogenesis, thus demonstrating that activated H-ras activates tumor angiogenesis through two distinct pathways. Finally, we show evidence for two forms of tumor dormancy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Animals
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Antigens, Polyomavirus Transforming / physiology*
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Cell Hypoxia
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Cell Line, Transformed
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Endothelial Growth Factors / genetics
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Endothelium / cytology
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Endothelium / metabolism
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Enzyme Inhibitors
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Gene Expression Regulation, Neoplastic
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Glycoproteins / metabolism
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H-2 Antigens / analysis
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Lymphokines / genetics
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Male
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Metalloendopeptidases / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Nude
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Neoplasms, Experimental / blood supply*
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Neovascularization, Pathologic / physiopathology*
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Oncogene Protein p21(ras) / physiology*
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Oncogenes / physiology*
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Phosphatidylinositol 3-Kinases
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
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Phosphotransferases (Alcohol Group Acceptor) / physiology
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RNA, Messenger / biosynthesis
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Simian virus 40 / immunology
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Tissue Inhibitor of Metalloproteinases
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Wortmannin
Substances
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Androstadienes
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Antigens, Polyomavirus Transforming
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Endothelial Growth Factors
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Enzyme Inhibitors
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Glycoproteins
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H-2 Antigens
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Lymphokines
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RNA, Messenger
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Tissue Inhibitor of Metalloproteinases
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Phosphatidylinositol 3-Kinases
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Phosphotransferases (Alcohol Group Acceptor)
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Metalloendopeptidases
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Oncogene Protein p21(ras)
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Wortmannin