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© The Rockefeller University Press, 0021-9525/2001//777 $5.00
The Journal of Cell Biology, Volume 152, Number 4, , 2001 777-784

The Plasminogen Activator Inhibitor PAI-1 Controls in Vivo Tumor Vascularization by Interaction with Proteases, Not Vitronectin

Khalid Bajou^a, Véronique Masson^a, Robert D. Gerard^b, Petra M. Schmitt^c, Valérie Albert^a, Michael Praus^b, Leif R. Lund^d, Thomas L. Frandsen^d, Nils Brunner^d, Keld Dano^d, Norbert E. Fusenig^e, Ulrich Weidle^f, Geert Carmeliet^g, David Loskutoff^c, Desiré Collen^b, Peter Carmeliet^b, Jean Michel Foidart^a, and Agnès Noël^a

^a Laboratory of Tumor and Developmental Biology, University of Liège, Tour de Pathologie (B23), B-4000 Liège, Belgium
^b Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
^c Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037
^d Finsen Laboratory, Rigshospitalet, DK-2100 Copenhagen, Denmark
^e Division of Carcinogenesis and Differentiation, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
^f Roche Diagnostics, D-82372 Penzberg, Germany
^g Laboratory of Experimental Medicine and Endocrinology (LEGENDO), Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
Laboratory of Tumor and Developmental Biology, University of Liège, Tour de Pathologie (B23), Sart-Tilman, B-4000 Liège, Belgium.32-4-366-29-3632-4-366-24-53

agnes.noel{at}ulg.ac.be

The plasminogen (Plg)/plasminogen activator (PA) system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumor cell migration. Consequently, urokinase-type PA (uPA)/plasmin antagonists are currently being developed for suppression of tumor growth and angiogenesis. Paradoxically, however, high levels of PA inhibitor 1 (PAI-1) are predictive of a poor prognosis for survival of patients with cancer. We demonstrated previously that PAI-1 promoted tumor angiogenesis, but by an unresolved mechanism. We anticipated that PAI-1 facilitated endothelial cell migration via its known interaction with vitronectin (VN) and integrins. However, using adenoviral gene transfer of PAI-1 mutants, we observed that PAI-1 promoted tumor angiogenesis, not by interacting with VN, but rather by inhibiting proteolytic activity, suggesting that excessive plasmin proteolysis prevents assembly of tumor vessels. Single deficiency of uPA, tissue-type PA (tPA), uPA receptor, or VN, as well as combined deficiencies of uPA and tPA did not impair tumor angiogenesis, whereas lack of Plg reduced it. Overall, these data indicate that plasmin proteolysis, even though essential, must be tightly controlled during tumor angiogenesis, probably to allow vessel stabilization and maturation. These data provide insights into the clinical paradox whereby PAI-1 promotes tumor progression and warrant against the uncontrolled use of uPA/plasmin antagonists as tumor angiogenesis inhibitors.

Key Words: angiogenesis • tumor invasion • proteolysis • migration • serine protease

© 2001 The Rockefeller University Press

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