Transforming growth factor-beta (TGF-β) is a pleiotropic factor, with several different roles in health and disease. TGF-β has been postulated as a dual factor in tumor progression, since it represses epithelial tumor development in early stages, whereas it stimulates tumor progression in advanced stages. During tumorigenesis, cancer cells acquire the capacity to migrate and invade surrounding tissues and to metastasize different organs. The urokinase-type plasminogen activator (uPA) system, comprising uPA, the uPA cell surface receptor, and plasminogen-plasmin, is involved in the proteolytic degradation of the extracellular matrix and regulates key cellular events by activating intracellular signal pathways, which together allow cancer cells to survive, thus, enhancing cell malignance during tumor progression. Due to their importance, uPA and its receptor are tightly transcriptionally regulated in normal development, but are deregulated in cancer, when their activity and expression are related to further development of cancer. TGF-β regulates uPA expression in cancer cells, while uPA, by plasminogen activation, may activate the secreted latent TGF-β, thus, producing a pernicious cycle which contributes to the enhancement of tumor progression. Here we review the specific roles and the interplay between TGF-β and uPA system in cancer cells and their implication in skin cancer. 1. Introduction Metastasis results from a complex molecular cascade which allows cancer cells to leave the site of the primary tumor mass and to disseminate to distant anatomical sites where they proliferate and form secondary tumour foci. Disseminated disease is the most usual cause of death in cancer patients and is, therefore, a very serious clinical problem [1]. Transforming growth factor-beta (TGF-β) has been postulated to have a dual role in tumour progression, acting as a tumour suppressor in early stages of carcinogenesis, and exerting a prooncogenic role in the last steps of the metastatic disease [2]. TGF-β induces the epithelial mesenchymal transition (EMT) of transformed cells, which contributes to tumour invasion and metastasis, and is frequently overexpressed in carcinoma cells [3–7]. To invade and metastasize, cancer cells traverse the surrounding extracellular matrix (ECM) expressing a set of ECM degrading proteases, such as urokinase-type plasminogen activator (uPA), which plays a key role in cells’ invasion and metastasis. uPA converts plasminogen to plasmin, which in turn can degrade a wide variety of ECM components and enable the tumour cells to penetrate the
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