Urokinase plasminogen activator system: a multifunctional role in tumor progression and metastasis

The urokinase plasminogen activator (uPA) system is central to a spectrum of biologic processes including fibrinoloysis, inflammation, atherosclerotic plaque formation, matrix remodeling during wound healing, tumor invasion, angiogenesis, and metastasis. Binding of uPA with its receptor (uPAR) initiates a proteolytic cascade that results in the conversion of plasminogen to plasmin. Plasmin through its own proteolytic function degrades a range of extracellular basement membrane components and activates others such as the metalloproteinases. Independent of catalytic activity, uPAR also is involved in cell signaling, interactions with integrins, cell motility, adhesion and invasion, and angiogenesis. Over expression of uPA or uPAR is a feature of malignancy and is correlated with tumor progression and metastasis. In contrast, inhibition of expression of these components leads to a reduction in the invasive and metastatic capacity of many tumors. Strategies that target uPA or its receptor with the aim of disrupting the interaction between the two or the ligand independent actions of uPAR include antisense technology, monoclonal antibodies, cytotoxic antibiotics, and synthetic inhibitors of uPA. Targeted therapy is a goal of future cancer treatment and the uPA system is a likely candidate for manipulation.