The plasmin/plasminogen system and cancer

Proteases play a central role in tissue repair and in the process of tumour growth and invasiveness. However, almost all of the proteolytic enzymes are secreted as inactive pro-proteases. With the exception of cathepsin D, which is capable of auto-activation, all the other proteases are activated by a common mechanism involving plasmin, which is itself derived from conversion of plasminogen, an ubiquitous pro-molecule. uPA initiates the conversion of plasminogen to the activated form, plasmin. The specific uPAR receptor is located on the external surface of the cell membrane. It does not have a trans-membrane component and is not linked to pathways of intracellular signal transduction. uPAR, however, can form heterodimers with other membrane molecules, such as growth factor receptors, cellular adhesion molecules etc. When these trans-membrane molecules form heterodimers with uPAR, they activate the pathways of signal transduction, with which they are associated. uPAR is essential for the activation of uPA, but also for cellular motility associated with integrin alpha v beta 3. The uPAR - alpha v beta 3 complex is formed on the leading edge of the lamellipodia of migrating cells (EMT positive cancerous epithelial cells and activated endothelial cells). PAI1 actively inhibits uPA activity and has a complex role in tumorigenesis: 1.in cell migration during invasion or angiogenesis, it detaches the uPAR - alpha v beta 3 complex which is bound to vitronectin and other ligands through uPA. This detachment at the posterior pole of motile cells results from the greater affinity of PAI1 at the uPA binding site on vitronectin. This allows uPAR to be internalised and its re-appearance at the leading edge of the cell. a second and very significant effect is its leading role in transient stabilisation of new capillaries through cooperation between endothelial cells and pericytes, which ensures that the new vessels are functional. This scientific evidence has been assessed by a European expert group with laboratory and clinical input and, in compliance with Hayes' criteria, has led to the establishment of uPA and PAI1as prognostic factors at the highest level of evidence (LOE-I) in breast cancer without node involvement. Together with hormone receptors ER PR and the membrane receptor HER2, these are the only parameters of LOE-I category for breast cancer, and they have appeared as such in international recommendations since 2007 and in the national recommendations of 2009.