In addition to the MMP family, the plasminogen activator/plasmin system has been implicated in tumor invasion and metastasis. Plasmin participates in tissue degradation and is activated from the inactive precursor plasminogen by two types of plasminogen activators – uPA (urokinase plasminogen activator) and tPA (tissue plasminogen activator) [
30]. The proteolytic activity of uPA plays a dominant role in cell migration, angiogenesis, and tumor metastases and is tightly regulated by proteolytic cleavage. It is released from various cell types as an inactive proenzyme (pro-uPA) which upon cleavage by proteinases becomes enzymatically active [
31]. uPA binds to a specific cell surface receptor the Urokinase Plasminogen Activator Receptor (uPAR). Upon binding, uPA converts the zymogen plasminogen to plasmin, an enzyme which degrades fibrin and numerous other components of the extracellular matrix, such as type IV collagen, fibronectin and laminin [
32]. This likely enables tumor cells to migrate through tissue barriers [
32,
33]. Several studies provided evidence that the expression of active uPA by malignant cells correlates with their invasive potential [
34]. Elevated levels of uPA/uPAR have been reported in numerous tumors, including pancreatic cancer [
25]. In patients with pancreatic cancer concomitant overexpression of uPA and uPAR was found to be associated with a shorter post-operative survival compared with those patients in whom only uPA or its receptor were overexpressed [
25]. In a recent study, the u-PA/u-PA receptor proteolytic system has been reported to be involved in the hepatocyte growth factor (HGF)-stimulated motility of pancreas cancer cells [
35]. HGF-induced cell motility is significantly reduced by inhibitors of u-PA proteolytic activity, such as antibodies neutralizing u-PA activity, plasminogen activator inhibitor 1 and amiloride [
35]. Additionally, anti-uPA antibodies injected into mice together with tumor cells caused a significant inhibition of metastasis formation, providing strong evidence for the involvement of this enzymatic system in tumor invasion and metastases.