Oncogenic H-Ras Stimulates Tumor Angiogenesis by Two Distinct Pathways

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-02, Vol.94 (3), p.861-866
Main Authors: Arbiser, Jack L., Moses, Marsha A., Fernandez, Cecilia A., Ghiso, Neil, Cao, Yihai, Klauber, Nancy, Frank, David, Brownlee, Michael, Flynn, Evelyn, Parangi, Sareh, Byers, H. Randolph, Folkman, Judah
Format: Article
Language:English
Subjects:
Androstadienes - pharmacology
Angiogenesis
Animals
Antigens, Polyomavirus Transforming - physiology
Biological Sciences
Cell Hypoxia
Cell Line, Transformed
Cell lines
Cells
Cellular biology
Endothelial cells
Endothelial Growth Factors - genetics
Endothelium - cytology
Endothelium - metabolism
Enzyme Inhibitors
Gene Expression Regulation, Neoplastic
Glycoproteins - metabolism
H-2 Antigens - analysis
Hypoxia
Lymphokines - genetics
Male
Medicin och hälsovetenskap
Messenger RNA
Metalloendopeptidases - metabolism
Mice
Mice, Inbred C57BL
Mice, Nude
Neoplasms, Experimental - blood supply
Neovascularization, Pathologic - physiopathology
Oncogene Protein p21(ras) - physiology
Oncogenes - physiology
Phosphatidylinositol 3-Kinases
Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors
Phosphotransferases (Alcohol Group Acceptor) - physiology
RNA, Messenger - biosynthesis
Simian virus 40 - immunology
Tissue Inhibitor of Metalloproteinases
Tumor cell line
Tumors
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
Viral tumor antigens
Wortmannin
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.3.861