title: 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.
authors.affiliation: The Finsen Laboratory, Copenhagen University Hospital, Copenhagen Biocenter, Ole Maaløes Vej 5, building 3.3, DK-2200 Copenhagen N, Denmark. ikl@finsenlab.dk
authors.forename: Ida K
authors.initials: IK
authors.lastname: Lund
authors.forename: Martin
authors.initials: M
authors.lastname: Illemann
authors.forename: Tine
authors.initials: T
authors.lastname: Thurison
authors.forename: Ib J
authors.initials: IJ
authors.lastname: Christensen
authors.forename: Gunilla
authors.initials: G
authors.lastname: Høyer-Hansen
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055293:Receptors, Urokinase Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator