The urokinase-type plasminogen activator system and its role in tumor progression

Abstract

In the multistage process of carcinogenesis, the key link in the growth and progression of the tumor is the invasion of malignant cells into normal tissue and their distribution and the degree of destruction of tissues. The most important role in the development of these processes is played by the system of urokinase-type plasminogen activator (uPA system), which consists of several components: serine proteinase – uPA, its receptor – uPAR and its two endogenous inhibitors – PAI-1 and PAI-2. The components of the uPA system are expressed by cancer cells to a greater extent than normal tissue cells. uPA converts plasminogen into broad spectrum, polyfunctional protease plasmin, which, in addition to the regulation of fibrinolysis, can hydrolyze a number of components of the connective tissue matrix (СTM), as well as activate the zymogens of secreted matrix metalloproteinases (MMР) – pro-MMР. MMРs together can hydrolyze all the main components of the СTM, and thus play a key role in the development of invasive processes, as well as to perform regulatory functions by activating and releasing from STM a number of biologically active molecules that are involved in the regulation of the main processes of carcinogenesis. The uPA system promotes tumor progression not only through the proteolytic cascade, but also through uPAR, PAI-1 and PAI-2, which are involved in both the regulation of uPA/uPAR activity and are involved in proliferation, apoptosis, chemotaxis, adhesion, migration and activation of epithelial-mesenchymal transition pathways. All of the above 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.