The urokinase receptor (CD87) represents a central mediator of growth factor-induced endothelial cell migration

Marina Poettler; Matthias Unseld; Judit Mihaly-Bison; Pavel Uhrin; Florian Koban; Bernd R. Binder; Christoph C. Zielinski; Gerald W. Prager

doi:10.1160/TH11-12-0868

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2012; 108(02): 357-366
DOI: 10.1160/TH11-12-0868

Endothelium and Vascular Development

Schattauer GmbH

The urokinase receptor (CD87) represents a central mediator of growth factor-induced endothelial cell migration

Authors

Marina Poettler

¹Clinical Division of Oncology, Department of Medicine I and Comprehensive Cancer Center Vienna, Medical University Vienna, Austria
Matthias Unseld

¹Clinical Division of Oncology, Department of Medicine I and Comprehensive Cancer Center Vienna, Medical University Vienna, Austria
Judit Mihaly-Bison

²Department of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology, Medical University Vienna, Austria
Pavel Uhrin

²Department of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology, Medical University Vienna, Austria
Florian Koban

²Department of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology, Medical University Vienna, Austria
Bernd R. Binder^*

²Department of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology, Medical University Vienna, Austria
Christoph C. Zielinski

¹Clinical Division of Oncology, Department of Medicine I and Comprehensive Cancer Center Vienna, Medical University Vienna, Austria
Gerald W. Prager

¹Clinical Division of Oncology, Department of Medicine I and Comprehensive Cancer Center Vienna, Medical University Vienna, Austria

Abstract

Summary

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 plas-minogen 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.

Keywords

uPA/plasminogen system - angiogenesis - endothelial cells - growth factors

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Referenzen

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