The Urokinase Plasminogen Activation System in Pancreatic Cancer: Prospective Diagnostic and Therapeutic Targets

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.

Metastatic phenotype and immunosuppressive tumour microenvironment in pancreatic ductal adenocarcinoma: Key role of the urokinase plasminogen activator (PLAU)

“…uPA and its cell surface receptor uPAR play a role in multiple stages of tumorigenesis, especially cancer progression (e.g., ECM degradation and EMT) ( 7 , 24 – 27 , 33 – 41 ). Moreover, clinical evidence demonstrates that high PLAU mRNA expression is associated with significantly worse clinicopathological characteristics and poor prognosis in PC patients ( 79 , 80 ).…”

“…The mean overall survival of the current standard treatment of FOLFIRINOX is 12.5 months, and that of Gemcitabine plus Abraxane, 10.3 months, P = 0.05 (3). Immunotherapies, individually or in combination with chemoradiotherapy or targeted therapy, have not made much progress in PDAC (4)(5)(6)(7), reflecting an urgent need to identify new biologically driven targets to limit PDAC progression, particularly metastasis, the primary driver of mortality in this disease.…”

“…The basal subtype is overrepresented amongst metastatic PDAC tumours, and it is distinguished by ECM-rich activated stroma, the upregulation of expression of laminins and keratins and enriched for genes associated with epithelial-mesenchymal transition (EMT) and TGF-b signalling (9). On the other hand, the classical PDAC signature is characterised by upregulation of a wide range of transcription factors, GATA4, GATA6, NKX2-2 and HNF1A, associated with pancreatic lineage differentiation (4)(5)(6)(7)(8). Clinicopathologically, basal-type tumours are poorly differentiated and correlate with a worse prognosis (median OS 10-19.2 months and DFS 4.6-10.9); these tumours are chemoresistant but may have a better response to adjuvant therapy (4)(5)(6)(9)(10)(11)(12)(13).…”

“…In normal cells ( 24 – 27 ), PLAU expression is very low and tightly controlled ( 7 , 23 , 28 ). However, PLAU and subsequently uPA expression is increased several-fold in tumour cells ( 23 , 29 – 31 ), which results in catalytic conversion of inactive plasminogen to plasmin.…”

“…Plasmin degrades extracellular matrix directly or indirectly via activation of precursor forms of matrix-degrading enzymes (matrix metalloproteinases) ( 32 ). Furthermore, in cancer cells, direct interaction of uPA with its receptor uPAR (encoded by PLAUR) facilitates the activation of multiple intracellular cell-signalling pathways, which regulate proliferation, migration, invasion, epithelial-mesenchymal transition, stem cell-like properties, release from states of dormancy, cell survival, chemoresistance, angiogenesis and vasculogenic mimicry ( 7 , 24 – 27 , 33 – 41 ) in cancer. All of which suggests a role as a master regulator in cancer development and progression.…”