The Urokinase Plasminogen Activator System: Role in Malignancy

The urokinase plasminogen activator (uPA) system consists of the serine protease uPA, its glycolipid-anchored receptor, uPAR and its 2 serpin inhibitors, plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor- 2 (PAI-2). Recent findings suggest that the uPA system is causally involved at multiple steps in cancer progression. In particular, uPA has been implicated in remodelling of the extracellular matrix, enhancing both cell proliferation and migration and modulating cell adhesion. Consistent with its role in cancer progression, multiple groups have shown that high levels of uPA in primary breast cancers are independently associated with adverse outcome. Paradoxically, high levels of PAI-1 also correlate with poor prognosis in patients with breast cancer. The prognostic value of uPA / PAI-1 in axillary node-negative breast cancer patients was recently validated using both a prospective randomised trial and a pooled analysis, i.e., in 2 different Level 1 Evidence studies. Assay of uPA and PAI-1 may thus help identify low risk node-negative patients for whom adjuvant chemotherapy is unnecessary. Finally, preclinical studies show that either inhibition of uPA catalytic activity or prevention of uPA binding to its receptor reduces tumor growth, angiogenesis and metastasis.