The Plasminogen Activation System in Tissue Remodeling and Cancer Invasion

Abstract

Plasminogen (Plg) is perhaps the most abundant and widely distributed protease zymogen in the organism. The local activation of Plg by the highly specific Plg activators is involved in a number of processes that require proteolytic restructuring of the extracellular milieu. We review the experimental evidence that implicates Plg activation in four very different tissue-remodeling events. These are wound healing, embryo implantation, mammary gland involution, and cancer metastasis. In all cases, the urokinase-type plasminogen activator (uPA) is produced by specialized cell populations within the remodeling tissue. In several of these processes, we have identified a functional overlap between the Plg activation system and one or more proteases of the matrix metalloprotease (MMP) family. We anticipate that similar functional redundancies are widespread in physiological as well as pathological proteolytic processes, and it therefore represents a challenge to identify the critical proteases for therapeutic targeting.