PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-1 IN CANCER - THERAPEUTIC AND PROGNOSTIC IMPLICATIONS

Degradation of the extracellular matrix prays a crucial role in cancer invasion. This degradation is accomplished by the concerted action of several enzyme systems, including generation of the serine protease p lasmin by the urokinase pathway of plasminogen activation, different t ypes of collagenases and other metalloproteinases, and other extracell ular enzymes. The degradative enzymes are involved also in tissue remo delling under non-malignant conditions, and the main difference appear s to be that mechanisms which regulates these processes under normal c onditions are defective in cancer. Specific inhibitors have been ident ified for most of the proteolytic enzymes, e.g. plasminogen activator inhibitors (PAI's) and tissue inhibitors of metalloproteinases (TIMP's ). It has been contemplated that these inhibitors counteracted the pro teolytic activity of the enzymes, thereby inhibiting extracellular tis sue degradation which in turn should prevent tumor cell invasion. This review focuses on plasminogen inhibitor type 1 (PAI-1). It is describ ed that PAI-1 is not produced by the epithelial cancer cell but by the stromal cells in the tumors, suggesting a concerted action between st roma and tumor cells in the processes controlling proteolysis in cance r. The specific localization of PAI-1 to the tumor stroma and in many cases to areas surrounding the tumor vessels has lead us to suggest th at PAI-1 serves to protect the turner stroma from the ongoing uPA-medi ated proteolysis. This hypothesis is supported by recent clinical data showing increased levels of PAI-1 in metastases as compared to the pr imary tumor as well as data demonstrating that high levels of PAI-1 in tumor extracts from breast, lung, gastric and ovarian cancer is assoc iated with a shorter overall survival. We further hypothesize that PAI -1 itself or uPA:PAI-1 interaction might represent an attractive new t arget for anti-invasive and antimetastatic therapy.