Open AccessOncogenic H-ras stimulates tumor angiogenesis by two distinct pathways
Author(s) -
Jack L. Arbiser,
Marsha A. Moses,
Cecilia Fernández,
Neil Ghiso,
Yihai Cao,
Nancy Klauber,
David A. Frank,
Michael Brownlee,
Evelyn Flynn,
Sareh Parangi,
H. Randolph Byers,
Judah Folkman
Publication year - 1997
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.94.3.861
Subject(s) - angiogenesis , downregulation and upregulation , matrix metalloproteinase , cancer research , biology , signal transduction , microbiology and biotechnology , kinase , tumor progression , chemistry , cancer , biochemistry , genetics , gene
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.