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 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.
Arbiser
J L
JL
Department of Dermatology, Harvard Medical School, Boston, MA 02115, USA.
Moses
M A
MA
Fernandez
C A
CA
Ghiso
N
N
Cao
Y
Y
Klauber
N
N
Frank
D
D
Brownlee
M
M
Flynn
E
E
Parangi
S
S
Byers
H R
HR
Folkman
J
J
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology*; D015687:Cell Hypoxia; D002461:Cell Line, Transformed; D016228:Endothelial Growth Factors / Q000235:genetics; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000378:metabolism; D006183:H-2 Antigens / Q000032:analysis; D008222:Lymphokines / Q000235:genetics; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D015689:Oncogene Protein p21(ras) / Q000502:physiology*; D009857:Oncogenes / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D013539:Simian virus 40 / Q000276:immunology; D019714:Tissue Inhibitor of Metalloproteinases; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000077191:Wortmannin
D000730:Androstadienes; D000952:Antigens, Polyomavirus Transforming; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D006183:H-2 Antigens; D008222:Lymphokines; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D008666:Metalloendopeptidases; D015689:Oncogene Protein p21(ras); D000077191:Wortmannin