The urokinase receptor as a potential target in cancer therapy.
The glycolipid-anchored receptor for urokinase-type plasminogen activator (uPAR) is essential for cell-surface associated plasminogen activation and is overexpressed at the invasive tumor-stromal microenvironment in many human cancers. In line with this, uPAR and uPA levels in both resected tumor tissue and plasma are of independent prognostic significance for patient survival in several types of human cancer. As the expression of both uPAR and its cognate protease ligand thus appears to be correlated with tumor malignancy, the uPA-uPAR interaction represents an attractive target for the development of either antagonists with possible anti-invasive effects or cytotoxic agents with anti-tumor effects. In this review we discuss recent achievements in the development of protein and peptide based drug candidates targeting uPAR. The majority of these compounds has been optimized for human uPAR and exhibits a pronounced species-specificity showing little or no reactivity with murine uPAR. This evidently complicates their application in preclinical intervention studies, since an intimate interplay between the tumor and its associated stroma is a distinct feature of the invasive phenotype of many human cancers. The virtues and drawbacks of various mouse tumor models as surrogates for human cancer are also discussed in relation to uPAR targeting.
Finsen Laboratory, Copenhagen University Hospital, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
John
J
Romer
Boye Schnack
BS
Nielsen
Michael
M
Ploug
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D008024:Ligands; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects*; D055293:Receptors, Urokinase Plasminogen Activator; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D008024:Ligands; C524898:PLAUR protein, human; D010455:Peptides; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator