The plasminogen activation system in tumor growth, invasion, and metastasis

Generation of the serine proteinase plasmin from the extracellular zymogen plasminogen can be catalyzed by either of two other serine proteinases, the urokinase- and tissue-type plasminogen activators (uPA and tPA). The plasm inogen activation system also includes the serpins PAI-1 and PAI-2, and the uPA receptor (uPAR). Many findings, gathered over several decades, strongl y suggest an important and causal role for uPA-catalyzed plasmin generation in cancer cell invasion through the extracellular matrix. Recent evidence suggests that the uPA system is also involved in cancer cell-directed tissu e remodeling. Moreover, the system also supports cell migration and invasio n by plasmin-independent mechanisms, including multiple interactions betwee n uPA, uPAR, PAI-1, extracellular matrix proteins, integrins, endocytosis r eceptors, and growth factors. These interactions seem to allow temporal and spatial reorganizations of the system during cell migration and a selectiv e degradation of extracellular matrix proteins during invasion. The increas ed knowledge about the plasminogen activation system may allow utilization of its components as targets for anti-invasive therapy.