Novel Patents and Cancer Therapies for Transforming Growth Factor-β and Urokinase Type Plasminogen Activator: Potential Use of Their Interplay in Tumorigenesis

Transforming growth factor beta1 (TGF-β1) plays different roles in health and disease. TGF-β1 has been assumed as a dual factor in tumor growth, since it can repress epithelial tumor development in early stages, while it acts as a tumor promoter in the late stages of tumor progression. Cancer cells, during carcinogenesis, acquire migration and invasion capacity which enables them to metastasize. The urokinase type plasminogen activator (uPA) system, comprised of uPA, the cell surface receptor (uPAR) and plasminogen-plasmin, is involved in the proteolytic degradation of the extracellular matrix and it also regulates several critical cellular events by its capacity to trigger the activation of intracellular signaling pathways. This enables the cancer cell survival, its dissemination, and enhancement of cell malignancy during tumor progression. The expression of both uPA and uPAR is finely regulated in normal development, but their expression is deregulated in cancer. TGF-β regulates uPA expression in cancer cells while uPA, by conversion of plasminogen to active form, plasmin, may release TGF-β1 from its latent state. Thus, these pathways cross-regulate each other by mutual feedback contributing to tumor progression. Here, we review the specific roles and the interplay between TGF-β1 and uPA system in cancer cells, the current cancer therapies and the novel patents focused mainly on uPA and TGF-β ligands and their cell surface receptors. Finally, with regard to the mutual activity of uPA and TGF-β1 in tumorigenesis, the aim of this chapter is to expose the potential of TGF-β1 and uPA systems to become combinatorial targets for therapies and patents.

Keywords: Activin A receptor type II-like kinase 5, ALK5, antisense oligonucleotides, anti-TGF-β antibodies, cancer, clinical trials, ECM, endoglin, extracellular matrix, fusion protein, microRNA, oligodeoxynucleotide, PAI, patents, plasminogen activator inhibitor, plasminogen-plasmin, soluble-uPAR, suPAR, TGF-β, therapy, transforming growth factor-β, transforming growth Factor-β receptor, Type I TβRI, Type II Transforming growth Factor-β receptor, TβRII, type III non-kinase TGF-β receptor, uPA, uPAR, urokinase type plasminogen activator, urokinase type plasminogen activator receptor.