Editorial [Hot Topic: The Plasminogen Activation System in Pathology: Use in Prognosis and Therapy (Guest Editor: Marie Ranson)]

Publisher： Bentham Science Publishers

E-ISSN： 1873-5592|12|12|1709-1710

ISSN： 1389-4501

Source： Current Drug Targets, Vol.12, Iss.12, 2011-11, pp. : 1709-1710

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Abstract

The classical physiological role of the plasminogen activation (PA) system is the dissolution of fibrin clots (fibrinolysis) by generation of plasmin [1]. It is now clear that fibrinolysis is not the sole function of the PA system. Indeed, this system contributes to the maintenance of cellular homeostasis, while deregulated expression of the PA system is linked to pathophysiological and pathological processes associated with wound healing, a range of inflammatory and infectious conditions, and tumour invasion and metastasis. Common to all these processes is the requirement for proteolytic activity and modulation of cellular adhesion and chemotaxis/migration allowing tissue remodelling and cellular invasion to occur. While over-expression of components of the PA system has been linked with metastatic cancer, opportunities have arisen whereby elements of the PA system are being used as prognostic markers for some malignant conditions. There is also compelling evidence for a fundamental role of the PA system in other disease states including neuropathology (such as stroke), cardiovascular disease and in chronic inflammatory and infectious diseases.The serine protease plasmin is generated from the abundant inactive zymogen plasminogen by two distinct but related serine proteases plasminogen activators [2-6]. Tissue-type plasminogen activator (tPA), through its high affinity to fibrin, has been primarily associated with vascular fibrinolysis whereas urokinase-type plasminogen activator (uPA) has been generally implicated in pericellular proteolysis resulting in extracellular matrix degradation allowing tissue invasion [2-6]. Both PAs require co-binding with their substrate plasminogen for efficient plasmin generation. In addition to fibrin interactions, tPA also co-binds with plasminogen, to a number of receptors on a variety of cell types as well as to denatured proteins formed after cell injury, especially in the brain [2]. Conversely, uPA binds with very high affinity and specificity to a GPI-anchored plasma membrane receptor (uPAR) [3-6]. The uPA-uPAR interaction also demonstrates strong species specificity which is an important consideration in designing antagonists of this interaction [3]. Plasmin directly degrades a wide variety of proteins and further contributes to ECM proteolysis by the activation of other classes of zymogen proteases [2-6]. Apart from the requirement for receptor co-localisation of the PAs and plasminogen, uncontrolled proteolysis is prevented through the precise and coordinated regulation of the PA system by cytokine and hormonal control of gene expression, specific inhibition of plasmin and PAs by 2-antiplasmin and plasminogen activator inhibitors (PAI-1, PAI-2), respectively, and by the clearance of the inhibited PAs by endocytosis receptors [7, 8]. The PA system also plays well established non-proteolytic roles in cell adhesion and migration in both cancer [5] and cardiovascular disease [9]. For example, uPAR associates with integrins and other transmembrane adapter proteins thereby initiating signaling pathways that affect cell adhesion, cytoskeletal structure and cell migration. This functional duality underscores the reach and diversity of the PA system by being able to modulate cell surface proteolysis, adhesion and the cell cytoskeleton. This is most clearly established for cancer whereby elevated cell surface uPA together with PAI-1 is now proven to be a critical marker of invasion and metastasis in most solid tumours and is the only breast cancer marker with level 1 evidence for a poor prognosis [10]. uPAR is also expressed in the tumour stroma which translates to an aggressive tumour phenotype associated with poor relapse-free survival [6]. Even though PAI-1 is an efficient uPA and tPA inhibitor, the mechanism linking PAI-1 expression to tumour progression/metastasis is mediated through well characterised interactions between PAI-1 and vitronectin or endocytosis receptors which promote cell