The Role of the Urokinase-Type Plasminogen Activator System In Tumor Progression

Abstract

In the multistage process of carcinogenesis, invasion of malignant cells into normal tissue and their distribution as well as the degree of tissue destruction are the key links in tumor growth and progression. The urokinase-type plasminogen activator system (uPA system) plays the most important role in the development of these processes. The uPA system consists of several components: serine proteinase—uPA, its receptor— uPAR and its two endogenous inhibitors – PAI-1 and PAI-2. The role of uPA, a highly specific protease, consists in triggering the processes performed by the uPA system, which result in destruction of connective tissue matrix (CTM) and basal membranes as well as activation of numerous extracellular and intracellular signaling pathways. uPA converts plasminogen into plasmin and in addition to the regulation of fibrinolysis, it can hydrolyze a number of CTM components and activate zymogens of secreted matrix metalloproteinases (MMРs)—pro-MMРs. MMРs can hydrolyze all the main СTM components and thus play a key role in the development of invasive processes, as well as to perform regulatory functions by activating and releasing from CTM a number of biologically active molecules involved in the regulation of the main processes of carcinogenesis. uPA, PAI-1 and PAI-2 not only regulate uPA/uPAR activity; they are also involved in proliferation, apoptosis, chemotaxis, adhesion, migration, and activation of epithelial-mesenchymal transition pathways. All the above mentioned processes are aimed at regulating invasion, metastasis and angiogenesis. The components of the uPA system are used as prognostic and diagnostic markers of many cancers, as well as serve as targets for anticancer therapy. Selective uPA inhibitors, uPAR peptide antagonists, monoclonal antibodies that can prevent uPA binding to uPAR, as well as antisense oligonucleotides directed against uPA and uPAR are intensively studied in this context as putative and actual pharmacological agents.