Toxin-Based Therapeutic Approaches

Shapira, Assaf; Benhar, Itai

Plasminogen is an inactive precursor of plasmin, a serine protease present in plasma and extracellular fluid and is active in the process of fibrinolysis and degradation of extracellular matrix (ECM) components [491] . One of the naturally occurring plasminogen activators is the urokinase-type plasminogen activator (uPA), a serine protease secreted as an inactive pro-enzyme (pro-uPA) that efficiently converted by plasmin or kallikrein into uPA, which in turn cleaves plasminogen to generate the active plasmin in a positive feed-back mechanism. The catalytic efficiency of these reactions is further increased upon binding of pro-uPA/uPA and plasminogen/plasmin to membranal receptors, resulting in reciprocal zymogen activation on the cell surface. The initial proteolytic event leading to the initiation of plasmin generation on the cell surface is still under study [492] [493] [494] [495] [496] [497] [498] . While quite restricted in normal tissues, expression of pro-uPA and its receptor, uPAR, was found to be elevated in a significant number of solid tumors. Moreover, the presence of this proteolytic system which confers the tumor mass with the ability to degrade ECM proteins is associated with increased tumor tissue invasiveness and metastatic potential [499, 500] .