Regulation of cancer invasion and vascularization by plasminogen activator inhibitor-1

Acquisition of invasive/metastatic potential through protease expression is a key event in tumor progression. The proteolytic enzyme plasmin is generated from the precursor plasminogen by the action of urokinase-type plasminogen activator (urokinase, uPA) or tissue-type plasminogen activator (tPA). Plasminogen activator inhibitor-1 or PAI-1 is the main inhibitor of uPA and tPA. High levels of components of this proteolytic system, including uPA and its cell surface receptor (uPAR), have been correlated with a poor prognosis for different cancers. It was therefore anticipated that PAI-1 expression would be associated with favorable outcome. Paradoxically, high rather than low PAI-1 levels predict poor survival of patients suffering from a variety of cancers. Recent observations indicate a much more complex role of PAI-1 in tumor progression and angiogenesis than initially expected. The exact mechanisms of this multifunctional molecule remain puzzling.