Abstract
Pancreatic cancer is a highly aggressive malignancy that features high recurrence rates and the poorest prognosis of all solid cancers. The urokinase plasminogen activation system (uPAS) is strongly implicated in the pathophysiology and clinical outcomes of patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic cancers. Overexpression of the urokinase-type plasminogen activator (uPA) or its cell surface receptor uPAR is a key step in the acquisition of a metastatic phenotype via multiple mechanisms, including the increased activation of cell surface localised plasminogen which generates the serine protease plasmin. This triggers multiple downstream processes that promote tumour cell migration and invasion. Increasing clinical evidence shows that the overexpression of uPA, uPAR, or of both is strongly associated with worse clinicopathological features and poor prognosis in PDAC patients. This review provides an overview of the current understanding of the uPAS in the pathogenesis and progression of pancreatic cancer, with a focus on PDAC, and summarises the substantial body of evidence that supports the role of uPAS components, including plasminogen receptors, in this disease. The review further outlines the clinical utility of uPAS components as prospective diagnostic and prognostic biomarkers for PDAC, as well as a rationale for the development of novel uPAS-targeted therapeutics.
Highlights
Despite advancements in drug discovery, pancreatic cancer continues to maintain the lowest patient survival rate of all major organ cancers, which has remained almost unchanged over the past four decades
The plasminogen receptors ENO1, histone histone 2B (H2B), plasminogen receptor KT (Plg-RKT), annexin A2 (ANXA2) and S100A10 have been shown to be expressed at the cell surface of human monocytes/macrophages, where they are involved in plasminogen activation and play an important role in the recruitment and migration of macrophages to tumour sites [207,208,209,210]
Considering the devastating prognosis that pancreatic ductal adenocarcinoma (PDAC) presents, characterised by one of the worst survival rates of all solid malignancies, the discovery and delivery of a biomarkerdriven drug would be a promising opportunity for its treatment
Summary
Despite advancements in drug discovery, pancreatic cancer continues to maintain the lowest patient survival rate of all major organ cancers, which has remained almost unchanged over the past four decades. Pancreatic ductal adenocarcinoma (PDAC), arising from multiple successive mutations in the ductal cells of the pancreas, accounts for ~92% of all pancreatic cancers and features a median patient survival of
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