The urokinase plasminogen activator system as a novel target for tumour therapy

Abstract

Substantial data have been collected for numerous types of solid cancer, including cancer of the breast, the gastrointestinal and urological tract, the lung, and the brain, demonstrating a strong clinical value of the plasminogen activation system in predicting disease recurrence and survival in cancer patients. Elevated levels of certain members of the plasminogen activation system, the serine protease uPA (urokinase-type plasminogen activator), its receptor (uPA-R; CD87), and inhibitor (PAI-1), in tumour tissue or blood emphasize their fundamental role in tumour invasion and metastasis and provide the rationale for novel therapeutic strategies. uPA, besides its proteolytic action toward the extracellular matrix, in concert with uPA-R, PAI-1, and integrins contributes to tumour cell proliferation, adhesion, and migration. Several technical methods of affecting tumour growth and metastasis by targeting the uPA-system in cancer patients at the gene and protein level have been explored: (1) antisense oligodeoxynucleotides to uPA, uPA-R, or PAI-1; (2) antisense oligonucleotides to signal transduction pathway components such as Rel (NF-κ B), affecting uPA but not PAI-1 synthesis; (3) viral vectors delivering genes for components of the plasminogen activation system; (4) soluble, recombinant uPA-R as a scavenger for uPA; (5) monoclonal antibodies directed to uPA or uPA-R blocking uPA/uPA-R interaction; (6) enzymatically inactive uPA to compete for active uPA binding to uPA-R; (7) linear and cyclic uPA-derived peptides to block uPA/uPA-R interaction; (8) toxins, coupled to uPA or fractions thereof to kill tumour cells; (9) naturally occurring inhibitors to uPA and its derivatives for inhibition of uPA proteolytic activity; and (10) synthetic inhibitors to uPA to inhibit uPA proteolytic activity. There is substantial hope that substances designed to affect or turn off the plasminogen activation system will eventually be administered to cancer patients thereby opening a new vista for tumour biology-based, individualized cancer therapy.