Transforming Growth Factor-Beta and Urokinase Type Plasminogen Interplay in Cancer

Transforming growth factor-beta (TGF-β) is well recognized as playing a double role in tumor progression. Its antitumor role takes place in the early stages of cancer development, when TGF-β acts as a repressor of epithelial tumor growth. In advanced stages of cancer development, TGF-β has a tumor stimulating role, acting concomitantly with the increase of cancer cell migration and metastasis. One of the critical features of cancer cells is their ability to migrate and invade the surrounding tissues leading to metastases in different organs. Cancer cells that leave the tumor to infiltrate neighboring tissues and ultimately overtake a distant organ, need a complex and fine-regulated mechanism to move through the barrier imposed by the extracellular matrix (ECM). Therefore, cancer cells express a set of proteinases which are involved in the degradation and turnover of ECM. In particular, the urokinase type plasminogen activator (uPA) and the uPA cell surface receptor play key cellular roles in the enhancement of cell malignance during tumor progression. In normal cells uPA system is finely regulated, while in tumor cells its expression and activity are dysregulated in a way to enhance cells' invasion capacity during tumor progression. TGF-β strongly regulates uPA in cancer from transcriptional expression to enzyme activity. In turn, uPA participates in the activation of secreted latent TGF-β, thus producing a malicious loop which contributes to tumor progression and metastasis. In this review we will analyze the main molecular mechanisms implicated in uPA regulation by TGF-β. Moreover, the specific roles and interaction between TGF-β and uPA system in cancer cells and their impact on tumorigenesis will be portrayed.