Regulation of Angiostatin Mobilization by Tumor-Derived Matrix Metalloproteinase-2

In recent years, the observation that many endogenous angiogenesis inhibitors are fragments of larger molecules has driven significant research efforts to understand the mechanisms by which these cryptic angiogenesis inhibitors are liberated. Our interest in this area stemmed from our discovery of angiostatin (1) , a 38 kDa internal fragment of plasminogen that is a specific inhibitor of capillary endothelial cell proliferation in vitro and angiogenesis in vivo. By inhibiting angiogenesis, angiostatin can induce the regression of a wide variety of malignant tumors (2) and can induce tumor dormancy defined by a dynamic equilibrium of tumor cell apoptosis and proliferation (3) . Angiostatin and other angiogenesis inhibitors are currently being evaluated in cancer patients in early clinical trials in the United States and around the world (4) . In this chapter, we will outline the reasoning and describe the experimental strategies that we employed in the course of identifying the enzymatic processing system that results in biologically active angiostatin. We will also discuss the clinical implications of our work with regards to the ongoing clinical trials of metalloproteinase inhibitors.