Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways

Jack L. Arbiser, Marsha A. Moses, Cecilia A. Fernandez, Neil Ghiso, Yihai Cao, Nancy Klauber, David Frank, Michael Brownlee, Evelyn Flynn, Sareh Parangi, H. Randolph Byers, Judah Folkman

Research output: Contribution to journalArticlepeer-review

427 Scopus citations


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 down-regulation 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.

Original languageEnglish (US)
Pages (from-to)861-866
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
StatePublished - Feb 4 1997
Externally publishedYes


  • angiosarcoma
  • endothelium
  • hemangioma
  • tumor dormancy

ASJC Scopus subject areas

  • General


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