The Urokinase-Plasminogen Activator System

The urokinase-plasminogen activator system consists of three main components, urokinase-plasminogen activator (uPA, a 53kDa serine protease), the uPA membrane-bound receptor (uPAR), and the uPA inhibitors, PAI-1 and PAl-2 5 3XB2,185 

The cathepsins are lysosomal proteases and cathepsin B, D, and L have been investigated for their role in tumor development and progression. 

Like other proteases, cathepsins are synthesized as high molecular weight precursors that require processing for activation. Cathepsin B (CB) is a thiol-dependent protease normally found in lysosomes, and is activated by cathepsin D (CD) and matrix metahoproteinases. Activated CB can in turn activate uPA and specific metalloproteinases. Cathepsin L (CL) is similar in specificity to that of CB however, it has little activity toward small molecular substrates. Cathepsin D, like CB, is a lysosomal protease however, CD belongs to the aspartyl group of proteases. 

A limited number of studies have associated high levels of CB in multiple tumor types with aggressive disease. All, with one exception, are retrospective studies with low numbers of patients. In the one large study (n 1500 patients), CB was shown to be an independent prognostic marker for both relapse-free and overall survival in breast cancer patients however, it is not as good a marker as uPA. 

The majority of data relating to the prognostic value of CD is in relation to breast cancer however, its usefulness in squamous cell carcinoma (SCC) of the head and neck. 

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Duffy MJ. 2004. The urokinase plasminogen activator system Role in malignancy. Curr Pharm Des 10 39-49. 

Jl. Jensen, M. K., Riisbro, R., Holten-Andersen, M. N., et al.. Collagen metabolism and enzymes of the urokinase plasminogen activator system in chronic myeloproliferative disorders Correlation between plasma-soluble urokinase plasminogen activator receptor and serum markers for collagen metabolism. Eur. J. Haematol. 71, 276-282 (2003). 

Ronne E, Behrendt N, Ellis V, Ploug M, Dano K, Hoyer-Hansen G. Cell-induced potentiation of the plasminogen activation system is abolished by a monoclonal antibody that recognizes the NH2-terminal domain of the urokinase receptor. FEBS Lett 1991 ... 

Andreasen PA, Kjoller L, Christensen L, et al. The Urokinase-type plasminogen activator system in cancer metastasis a review. Int J Cancer 1997 72 ... 

Urokinase plasminogen activator (uPA)/plasminogen activator inhibitor (PAI-1) are part of the plasminogen activating system, which includes the receptor for uPA and other inhibitors (PAI-2 and PAI-3). This system has been shown experimentally to be associated with invasion, angiogenesis, and metastasis.Low levels of both markers are associated with a sufficiently low risk of recurrence (especially in HR-positive women who will receive adjuvant endocrine therapy) that chemotherapy will only contribute minimal additional benefit. Furthermore, Cytoxan-, methotrexate-, and... 

Ol. Odet, F., Guyot, R., Leduque, P., and Le Margueresse-Battistoni, B., Evidence for similar expression of protein C inhibitor and the urokinase-type plasminogen activator system during mouse testis development. Endocrinology 145, 1481-1489 (2004). 

Tissue Plasminogen Aetivator (tPA). While streptokinase and urokinase can effectively induce clot dissolution in the majority of patients if given early, they lack clot specificity. Treatment with these enzymes results in a systemic lytic state attributable to their degradative action on circulating fibrinogen. Tissue plasminogen activator (tPA) was developed to achieve rapid and specific thrombolysis. 

The hypothesis that stress can modulate MMP expression is also supported by studies in mice. Using social isolation as a stressor, the mRNA levels of MMP-2, MMP-9, matrix-type matrix metalloproteinase-1 (MT1-MMP), and urokinase-type plasminogen activator were higher in the tumor and liver tissues of the isolated mice than in control mice.91 Furthermore, a recent study has shown that restraint stress causes an increase in expression of the plasminogen activator inhibitor-1, another key player in the plas-minogen/plasmin enzyme system in mice.92 As these enzymes have been described to have functions besides their role in ECM remodeling,93 studies on stress-related effects on MMP/TIMP balance have implications in the relationship between stress and cancer initiation and progression.. 

The role of the fibrinolytic system is to dissolve any clots that are formed within the intact vascular system and so restrict clot formation to the site of injury. The digestion of the fibrin and hence its lysis is catalysed by the proteolytic enzyme, plasmin, another serine proteinase. Plasmin is formed from the inactive precursor, plasminogen, by the activity of yet other proteolytic enzymes, urokinase, streptokinase and tissue plasminogen activator (tPA) which are also serine proteinases. These enzymes only hydrolyse plasminogen that is bound to the fibrin. Any plasmin that escapes into the general circulation is inactivated by binding to a serpin (Box 17.2). 

Regulation of the fibrinolytic system is useful in therapeutics. Increased fibrinolysis is effective therapy for thrombotic disease. Tissue plasminogen activator, urokinase, and streptokinase all activate the fibrinolytic system (Figure 34-3). Conversely, decreased fibrinolysis protects clots from lysis and reduces the bleeding of hemostatic failure. Aminocaproic acid is a clinically useful inhibitor of fibrinolysis. Heparin and the oral anticoagulant drugs do not affect the fibrinolytic mechanism. 

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