The Urokinase Plasminogen Activator System: Role in Malignancy

Abstract

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.

An urokinase receptor antagonist that inhibits cell migration by blocking the formyl peptide receptor

“…Stimulation of RBL-2H3/ETFR cells with fMLF induces activation of several protein kinases, including MAP kinases [21]. As expected, RBL-2H3/ETFR cell exposure to 10 nM fMLF for 5 or 10 min triggered a time-dependent increase of ERK1/2 phosphorylation.…”

“…In this respect, efforts have been made to interfere with the uPA/uPAR or integrin/uPAR interactions [9,21,22]. To the best of our knowledge, pER-ERY-NH 2 is the first uPAR inhibitor that specifically impairs the uPAR/FPR interaction.…”

Glioblastoma: Current Chemotherapeutic Status and Need for New Targets and Approaches

“…Together with MMP-2, and MMP-9, MT1-MMP imparts an invasive phenotype to glioblastoma multiforme Nakada et al, 2001). Urokinase plasminogen activator and receptor (uPA/uPAR) system is important in cancer cell migration and invasion (D'Alessio & Blasi, 2009;Duffy, 2004). Once this system is activated, it converts the inactive plasminogen to the active plasmin.…”

Gene therapy targeting to tumor endothelium

“…17 These proteins are upstream of complex proteolytic cascades. The leakiness of tumor vessels induced by VEGF allows extensive diffusion of fibrin 18 and other proteins of the coagulation cascade into the extracellular matrix.…”