The plasminogen activation system is composed of plasminogen activators, tissue- type ( t-PA) and urokinase- type (u-PA) which convert the zymogen plasminogen to active plasmin. Plasmin is a broad specificity enzyme that degrades fibrin and several proteins of the extracellular matrix, and is able to activate pro-metalloproteinases and growth factors (TGF- β, bFGF, VEGF). T-PA and u-PA activity is controlled by plasminogen activator inhibitor type-1 (PAI-1) and type-2 (PAI-2) belonging to the serpin family. T-PA plays a crucial role in intravascular fibrinolysis, u-PA is involved in cell mediated proteolysis. U-PA binds a specific, high affinity cell-surface receptor (u-PAR) increasing u-PA activity and directing plasmin activity to the cell surface.

Recent studies showed that the agressive, invasive phenotype of cancer cells is strongly tied to plasminogen activation system. Many clinical and experimental studies have proved that the high expression of u-PA, u-PAR and PAI-1 was closely related to the poor prognosis for different cancers (brest, lung, colon, ovarian, gastric, kidney, liver, colorectal)

Several functions of u-PA, u-PAR and PAI-1 have been shown to be involved in the invasive behaviour of cancer cell. U-PA/u-PAR influence cell migration via proteolytic mechanism i.e. plasmin generation and non-proteolytic mechanism i.e. chemotaxis, adhesion, proliferation. The u-PA/u-PAR complex is strongly involved in the attachment/detachment process of cancer cells, a mechanism obviously essential for cell migration. Interaction of u-PA/u-PAR with PAI-1 induces internalization of the ternary complex which subsequently results in intracellular degradation of u-PA and PAI-1, while u-PAR is recycled to the cell surface . By this the proteolytic activity is efficiently reorganized on the cell surface enabling pericellular proteolysis and degradation of the extracellular matrix. Binding of u-PA to cell surface associated u-PAR leads to activation of various intracellular signaling molecules such as tyrosine-, serine-protein kinases, stimulates carcinoma cell migration by enhancing integrin-mediated signal transduction. PAI-1 may control tumor angiogenesis by regulating proteolytic and non-proteolytic events in endothelial cell migration that may depend on the expression by these cells of integrins, u-PA uPAR , on endocytosis of u-PA/u-PAR complex , as well on the composition of the extracelllar matrix. PAI-1 could inhibit apoptosis in cancer cell. Recent observations indicate a much more complex role of PAI-1 in tumor progression than initially expected.

The plasminogen activation system represents a novel target for tumor- biology based therapy by interfering with the expression of u-PA, u-PAR and PAI-1 at gene or protein level.

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