The urokinase receptor (CD87) represents a central mediator of growth factor-induced endothelial cell migration.
Angiogenesis, the sprouting of blood vessels form pre-existing vasculature after injury or in neoplastic diseases, is initiated by growth factor-induced endothelial cell migration. Recently, the major angiogenic growth factor VEGF165 has become the target of therapeutic interventions. However, this approach has been clinically proven to be of limited efficacy, which might be due to the fact that tumour angiogenesis is not only induced by VEGF, but also by a variety of other growth factors. Thus, the identification of a common downstream mediator of growth-factor-induced endothelial cell migration is mandatory to effectively interfere with (tumour-) angiogenesis. We found that the urokinase-type plasminogen activator (uPA)-system, which affects proteolytic as well as adhesive capacities, represents an essential regulatory mechanism in growth factor-induced endothelial cell migration and invasion. This mechanism was not limited to VEGF165, but mediated pro-angiogenic endothelial cell behaviour induced by various growth factors. Thus, VEGF165, VEGF-E, FGF-2, EGF as well as HGF induced a PI3k-dependent activation of pro-uPA when bound to uPAR, which led to an increase in cell surface fibrinolytic activity. As a consequence, uPAR became internalised and redistributed via LDLR-proteins. Interference with these events led to a reduced migratory response of endothelial cells towards VEGF  in vitro as well as endothelial cell invasion in vivo. These data give first evidence that the uPA-system, which represents the only level-of-evidence-1 cancer biomarker system for prognosis and/or prediction in node negative breast cancer, might directly affect (tumour-) angiogenesis.
Clinical Division of Oncology, Department of Medicine I and Comprehensive Cancer Center Vienna, Medical University Vienna, Austria.
Marina
M
Poettler
Matthias
M
Unseld
Judit
J
Mihaly-Bison
Pavel
P
Uhrin
Florian
F
Koban
Bernd R
BR
Binder
Christoph C
CC
Zielinski
Gerald W
GW
Prager
D014408:Biomarkers, Tumor; D002460:Cell Line; D002465:Cell Movement; D042783:Endothelial Cells / Q000166:cytology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005342:Fibrinolysis; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008833:Microcirculation; D018715:Microscopy, Video / Q000379:methods; D018919:Neovascularization, Physiologic; D011379:Prognosis; D055293:Receptors, Urokinase Plasminogen Activator / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D014408:Biomarkers, Tumor; D036341:Intercellular Signaling Peptides and Proteins; C524898:PLAUR protein, human; D055293:Receptors, Urokinase Plasminogen Activator; D042461:Vascular Endothelial Growth Factor A