uPAR as Anti-Cancer Target: Evaluation of Biomarker Potential, Histological Localization, and Antibody-Based Therapy

Abstract

Degradation of proteins in the extracellular matrix is crucial for the multistep process of cancer invasion and metastasis. Compelling evidence has demonstrated the urokinase receptor (uPAR) and its cognate ligand, the urokinase plasminogen activator (uPA), to play critical roles in the concerted action of several proteolytic systems in generation of a high proteolytic potential required for tissue remodeling processes. uPAR is additionally cleaved by uPA on the cell surface, liberating domain I, resulting in abrogated pericellular proteolysis. The expression of both uPAR and uPA is significantly up-regulated during cancer progression and is primarily confined to the tumor-associated stromal compartment. Furthermore, both uPAR and uPA have proven to be prognostic markers in several types of cancer; high levels indicating poor survival. The cleaved forms of uPAR are also prognostic markers, and a potential diagnostic and predictive impact of the different uPAR forms has been reported. Hence, pericellular proteolysis seems to be a suitable target for anti-cancer therapy and numerous approaches have been pursued. Targeting of this process may be achieved by preventing the binding of uPA to uPAR on the cell surface and/or by direct inhibition of the catalytic activity of uPA. Both strategies have been pursued and inhibition of these functions has shown effect in xenogenic cancer models. Pericellular proteolysis has also been inhibited in vivo in mouse models of wound healing and hepatic fibrinolysis using mouse monoclonal antibodies (mAbs) against mouse uPA or uPAR. These reagents will target uPA and uPAR in both stromal cells and cancer cells, and their therapeutic potential can now be assessed in syngenic mouse cancer models.

Administration of Recombinant Soluble Urokinase Receptor Per Se Is Not Sufficient to Induce Podocyte Alterations and Proteinuria in Mice

“…6 High circulating levels of suPAR, however, have been observed in other human diseases, but without the FSGS phenotype (e.g., elevated suPAR is a general biomarker for poor prognosis in many pathologic conditions, including some cancers). 7,8 In addition, Maas et al compared serum uPAR levels in patients with FSGS with levels in minimal change diseases and failed to identify a significant association between levels and diagnosis. 9 Although this investigation may have lacked statistical power, 10 an independent study by Bock et al 11 recently reached the same conclusion.…”

A Flexible Multidomain Structure Drives the Function of the Urokinase-type Plasminogen Activator Receptor (uPAR)

“…Several studies have also implicated uPAR in pathological conditions, such as focal segmental glomerulosclerosis (2, 3), paroxysmal nocturnal hemoglobinuria (4), rheumatoid arthritis (5), and cancer invasion and metastasis (6 -8). In the latter group of diseases, uPAR is predominantly expressed by cells residing in the tumor-stromal interface of the invasive front, and high levels of uPAR in either resected tumor tissue or circulating in blood are concordantly a general biomarker for poor prognosis in many types of human cancer (9). Following this line of evidence, several intervention strategies targeting uPAR have been developed, and some have shown promising therapeutic effects in preclinical mouse model systems (10 -13).…”

A novel peptide blocking cancer cell invasion by structure-based drug design

“…Several researchers have identified, synthesized and preclinically examined several compounds acting as potential inhibitors of the uPA-uPAR interaction. The following are currently promising anti-invasive/metastatic agents: protease inhibitors (8,13), small molecular peptides (13)(14)(15)(16)(17)24), antibodies (34,36) and siRNA/shRNA 32). Some of these have been evaluated in in vivo pharmacokinetic and efficacy studies in an animal cancer metastasis model.…”

“…Indeed, various treatment strategies including selective inhibitors of uPA activity (6-13), specific antagonistic peptides that block uPA-uPAR protein-protein interaction (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), shRNA-uPAR-mediated silencing (5,(25)(26)(27)(28)(29)(30)(31)(32), or inhibitory antibodies against uPA or uPAR (33-36) have been investigated in promising preclinical and clinical trials. Although uPAR promotes cancer progression independently of protease activation, scavenging the active uPA or blocking its function leads to reduced tumor progression and may show be promising for prolonging patient survival (37).…”