The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin

Implications for antiangiogenic strategies

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

Research output: Contribution to journalArticle

278 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)777-784
Number of pages8
JournalJournal of Cell Biology
Volume152
Issue number4
DOIs
StatePublished - Feb 19 2001

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Vitronectin
Plasminogen Inactivators
Peptide Hydrolases
Urokinase-Type Plasminogen Activator
Neoplasms
Fibrinolysin
Plasminogen
Proteolysis
Cell Movement
Integrin alphaVbeta3
Angiogenesis Inhibitors
Plasminogen Activators
Plasminogen Activator Inhibitor 1
Tissue Plasminogen Activator
Integrins
Extracellular Matrix
Endothelial Cells

Keywords

  • Angiogenesis
  • Migration
  • Proteolysis
  • Serine protease
  • Tumor invasion

ASJC Scopus subject areas

  • Cell Biology

Cite this

The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin : Implications for antiangiogenic strategies. / Bajou, Khalid; Masson, Véronique; Gerard, Robert D.; Schmitt, Petra M.; Albert, Valérie; Praus, Michael; Lund, Leif R.; Frandsen, Thomas L.; Brunner, Nils; Dano, Keld; Fusenig, Norbert E.; Weidle, Ulrich; Carmeliet, Geert; Loskutoff, David; Collen, Desiré; Carmeliet, Peter; Foidart, Jean Michel; Noël, Agnès.

In: Journal of Cell Biology, Vol. 152, No. 4, 19.02.2001, p. 777-784.

Research output: Contribution to journalArticle

Bajou, K, Masson, V, Gerard, RD, Schmitt, PM, Albert, V, Praus, M, Lund, LR, Frandsen, TL, Brunner, N, Dano, K, Fusenig, NE, Weidle, U, Carmeliet, G, Loskutoff, D, Collen, D, Carmeliet, P, Foidart, JM & Noël, A 2001, 'The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin: Implications for antiangiogenic strategies', Journal of Cell Biology, vol. 152, no. 4, pp. 777-784. https://doi.org/10.1083/jcb.152.4.777
Bajou, Khalid ; Masson, Véronique ; Gerard, Robert D. ; Schmitt, Petra M. ; Albert, Valérie ; Praus, Michael ; Lund, Leif R. ; Frandsen, Thomas L. ; Brunner, Nils ; Dano, Keld ; Fusenig, Norbert E. ; Weidle, Ulrich ; Carmeliet, Geert ; Loskutoff, David ; Collen, Desiré ; Carmeliet, Peter ; Foidart, Jean Michel ; Noël, Agnès. / The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin : Implications for antiangiogenic strategies. In: Journal of Cell Biology. 2001 ; Vol. 152, No. 4. pp. 777-784.
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abstract = "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.",
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AU - Gerard, Robert D.

AU - Schmitt, Petra M.

AU - Albert, Valérie

AU - Praus, Michael

AU - Lund, Leif R.

AU - Frandsen, Thomas L.

AU - Brunner, Nils

AU - Dano, Keld

AU - Fusenig, Norbert E.

AU - Weidle, Ulrich

AU - Carmeliet, Geert

AU - Loskutoff, David

AU - Collen, Desiré

AU - Carmeliet, Peter

AU - Foidart, Jean Michel

AU - Noël, Agnès

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