Summary Recent studies have shown that elevated levels of urokinase plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1) in breast cancer correlate with an increased risk of a reduced relapse-free survival time and shortened overall survival times. Urokinase PA and PAI-I are independent prognostic indicators for breast cancer (Goldfarb and Liotta, 1986). Among the diverse extracellular proteolytic enzymes produced by tumours, urokinase plasminogen activator (uPA) is considered to play a pivotal role in tissue invasion, vascular invasion and formation of metastases (Dano et al., 1985).Tumour cells synthesise and secrete uPA as an inactive proenzyme (pro-uPA) (Stump, 1986), which binds to specific receptors on the cell surface (Vasalli et al., 1985). After binding, pro-uPA is activated by cathepsin B or plasmin (Kobayashi et al., 1990). Receptor-bound active uPA converts plasminogen to plasmin. Subsequently, plasmin is also bound to a different receptor on the tumour cell surface (Miles and Plow, 1988). Plasmin then degrades components of the stroma (e.g. fibrin, fibronectin, proteoglycans, laminin), and may activate procollagenase type IV, which then degrades collagen type IV, a major part of the basement membrane (Dvorak, 1986). Thus uPA promotes the dissolution of the tumour matrix and the basement membrane, which is a prerequisite for invasion and metastases. This implies that the proteolytic activity of uPA also causes a degradation of vessel walls. Vessel wall dissolution is one of the first steps in neovascularisation (Mahadevan and Hart, 1990). Furthermore, some ECM molecules become angiogenic after hydrolytic degradation (West et al., 1985
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