ReviewDiversity and functional evolution of the plasminogen activator system
Introduction
Urokinase type plasminogen activator (PLAU or uPA), and its receptor (uPAR), the substrate plasminogen (Plg), and the plasminogen activator inhibitor 1 and 2 (PAI1 and PAI2) also known as serpine 1 and serpine 2 together make the plasminogen activator system [1]. This system is a major regulator of the tumor microenvironment and is crucially involved in the metastatic process in many cancers. uPA system has a wide range of targets along with prominent location in the proteolytic network of tumors and that’s why this system attracted attention of many research groups [1]. The plasminogen activator systems are involved in various physiological processes like tissue remodeling [2], but in addition to this, uPA system is involved in pathogenesis of vascular diseases such as atherosclerosis, thromboembolic disorders and stroke [3]. Research on plasminogen system intensified after urokinase was found in the urine of cancer patients in 1960 [4]. Moreover, another study in 1988 in breast cancer patients for the first time revealed uPA as a prognostic marker for survival in cancer [5]. The receptor of uPA i.e. uPAR was discovered by Vassalli et al in 1985 and its association with cancer was established in 1991 by Ossowski et al [6,7]. Since then extensive research has been undertaken on its role in cancer invasion and metastasis. Two types of plasminogen activator are found in plasminogen activator system viz., tissue type plasminogen activator (tPA) and urokinase type plasminogen activator (uPA). The former is present in both normal and some malignant tissues and is mainly involved in conversion of plasminogen to plasmin during dissolution of blood clot, while uPA is mainly associated with malignancy of cancer and plays role in pericellular proteolysis during cell migration and tissue remodeling [8]. Furthermore, it is well established now that higher expression level of both uPA and uPAR enhance tumor growth and metastasis and correlated with poor prognosis [9,10]. Though both tPA and uPA can activate inactive plasminogen to active plasmin, uPA has been extensively studied in cancer metastasis.
Section snippets
uPA is a multifaceted protein
uPA is a serine protease with molecular weight of approximately 50,000 Da which is released from the cells as a single chain zymogen pro-uPA, a non-active 411 amino acid glycoprotein which after cleavage at K158–I159 forms two-chain high molecular weight uPA (HMW uPA) [11]. This conversion is catalyzed by plasmin, blood coagulation factor XIIa, plasma kallikrein, cathepsin B, cathepsin L, T cell–associated serine proteinase, nerve growth factor-γ and prostate specific antigen [[12], [13], [14],
Plasminogen activator inhibitors
Serine proteinase inhibitors (serpins) constitute a superfamily. These inhibitors contain a surface-exposed reactive center peptide loop, having reactive center peptide bond. This peptide bond is actually pseudo-substrate and it helps to trap targeted proteinases in inactive form in a stable complex of 1:1 stoichiometry. Interaction between the large central β-sheet A of the serpin and the reactive center loop results in the formation of this complex [108,109]. Three proteinase inhibitors named
Role of plasminogen activator in stemness of cancer cell
Stemness of a cell is characterized by the capability of a cell to perpetuate its lineage, producing differentiated cells and to interact with its environment to keep the balance between quiescence, proliferation, and regeneration [117]. These are properties mainly display by adult stem cells while cancer stem cells (CSCs) show stemness to sustain cancer progression [117]. Experiments conducted by many researchers revealed that plasminogen activator system plays a crucial role in stemness of
Role of stromal cells in plasminogen activation system
Initially the role of plasminogen activator and other protease systems in cancer were studied in transformed cultured cells or established cell lines [121,122]. Researchers at that time completely believed that cancer cells produced these proteases in tumor tissues, an observation that was supported by research on transplanted tumors [12,123]. However, these findings were strongly challenged by several studies with human colon cancer. The mRNA for uPA could be shown only in stromal cells in
Endocytosis and recycling of uPA and uPAR
For the effective pericellular proteolysis and cell invasion, an important step is endocytosis and recycling of glycosylphosphatidylinositol (GPI) anchored uPAR [1]. Moreover, it is demonstrated that uPA-uPAR complex alone is quickly endocytosed and degraded in comparison with uPAR-bound uPA-PAI-1 complex [140]. This was further confirmed by many researchers [102,141,142]. It is also reported that uPAR expressing cells were capable to endocytose the uPA-PAI-1 complex [Fig 1] [143]. A clathrin
uPA-uPAR signaling
Currently, it is very well established that uPA-uPAR complex has many roles apart from the regulation of extracellular proteolysis. When uPA binds to uPAR it activates a cascade of intracellular signaling molecules that promote proliferation, differentiation, adhesion, migration, invasion and cell survival [1,[150], [151], [152]]. Signaling by uPA and uPAR begins when this complex interacts with trans-membrane proteins such as integrin family proteins, receptor tyrosine kinases and chemotactic
Plasminogen activator system and cancer
Experiments conducted on model systems have revealed that plasminogen activator system plays a key role in cancer progression [168]. Earlier the classical function of uPA was ECM degradation by which it promotes cancer invasion and metastasis. Currently the function of uPA is not limited to only ECM degradation but there are additional activities indicating its role in the proliferation and spreading of cancer [136,169]. The most important step for invasion and metastasis is to degrade and
Plasminogen system and EMT
Most of the cancer related deaths are due to metastasis and epithelial-to-mesenchymal transition (EMT) is an integral part of this. EMT is a multistage trans-differentiation process in which highly polarized epithelial cells acquire invasive and migratory potential during pathological and physiological processes accompanying cancer progression, embryonic development and wound healing [226,227]. Many developmental transcription factors such as Twist1/2 and Six, Snail 1/2, TGF-β and Wnt/β-catenin
Evolution of plasminogen activator system
As discussed above, the plasminogen activator system comprises of an enzymatic cascade known to play a key role in the regulating fibrin degradation, matrix turnover and cell invasion. Members of the plasminogen activator system are serine proteases. Serine proteases performed diverse array of cellular and physiological functions such as protein processing and tissue remodeling, fertilization, embryonic development, blood clotting and fibrinolysis, digestive and degradative processes, [245].
Conclusion
There is substantial evidence in the literature for important role of uPA system in cancer cell growth, migration, invasion and metastasis. The uPA system is an attractive target for cancer therapeutics because of its crucial role in cancer progression and metastasis. In this review we have attempted to illustrate the role of uPA system in cancer and metastasis. We have also summarized the role of uPA signaling in EMT of cancer cells. We believe that the inhibition of these signaling pathways
Conflict of interest
The authors declare that they have no conflict of interest.
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