The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin: Implications for antiangiogenic strategies

The plasminogen (Plg)/plasminogen activator (PA) system plays a key role in cancer progression, presumably via mediating extracellular matrix degradat ion 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 (PA I-1) are predictive of a poor prognosis for survival of patients with cance r. We demonstrated previously that PAI-1 promoted tumor angiogenesis, but b y an unresolved mechanism. We anticipated that PAI-1 facilitated endothelia l cell migration via its known interaction with vitronectin (VN) and integr ins. However, using adenoviral gene transfer of PAI-1 mutants, we observed that PAI-1 promoted tumor angiogenesis, not by interacting with VN, but rat her by inhibiting proteolytic activity, suggesting that excessive plasmin p roteolysis prevents assembly of tumor vessels. Single deficiency of uPA, ti ssue-type PA (tPA), uPA receptor, or VN, as well as combined deficiencies o f uPA and tPA did not impair tumor angiogenesis, whereas lack of Pig reduce d it. Overall, these data indicate that plasmin proteolysis, even though es sential, 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 angiogenes is inhibitors.