Plasminogen activator inhibitor type 1 in cancer: therapeutic and prognostic implications

Degradation of the extracellular matrix plays a crucial role in cancer invasion. This degradation is accomplished by the concerted action of several enzyme systems, including generation of the serine protease plasmin by the urokinase pathway of plasminogen activation, different types of collagenases and other metalloproteinases, and other extracellular enzymes. The degradative enzymes are involved also in tissue remodelling under non-malignant conditions, and the main difference appears to be that mechanisms which regulates these processes under normal conditions are defective in cancer. Specific inhibitors have been identified 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 proteolytic activity of the enzymes, thereby inhibiting extracellular tissue degradation which in turn should prevent tumor cell invasion. This review focuses on plasminogen inhibitor type 1 (PAI-1). It is described that PAI-1 is not produced by the epithelial cancer cell but by the stromal cells in the tumors, suggesting a concerted action between stroma and tumor cells in the processes controlling proteolysis in cancer. 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 that PAI-1 serves to protect the tumor stroma from the ongoing uPA-mediated proteolysis. This hypothesis is supported by recent clinical data showing increased levels of PAI-1 in metastases as compared to the primary tumor as well as data demonstrating that high levels of PAI-1 in tumor extracts from breast, lung, gastric and ovarian cancer is associated with a shorter overall survival.(ABSTRACT TRUNCATED AT 250 WORDS)