Experimental and Clinical Evidence Supports the Use of Urokinase Plasminogen Activation System Components as Clinically Relevant Biomarkers in Gastroesophageal Adenocarcinoma

SIMPLE SUMMARY: Patients with gastric and oesophageal adenocarcinomas (GOCs) have short life expectancies as their tumours spread to other sites early. This is facilitated by the increased expression of the urokinase plasminogen activation system (uPAS); a feature of the majority of GOCs. There is increasing appreciation of the importance of uPAS expression in a range of cell types within the tumour microenvironment. Abundant clinical evidence indicates that altered expression of uPAS proteins is associated with worse outcomes, including time to tumour recurrence and patient survival. Emerging technologies, including liquid biopsy, suggest a role of uPAS for the detection of circulating tumour cells, which are responsible for the dissemination of cancers. We review and summarise pre-clinical and clinical data that supports the use of uPAS as a biomarker in GOC. ABSTRACT: Gastric and oesophageal cancers (GOCs) are lethal cancers which metastasise early and recur frequently, even after definitive surgery. The urokinase plasminogen activator system (uPAS) is strongly implicated in the invasion and metastasis of many aggressive tumours including GOCs. Urokinase plasminogen activator (uPA) interaction with its receptor, urokinase plasminogen activator receptor (uPAR), leads to proteolytic activation of plasminogen to plasmin, a broad-spectrum protease which enables tumour cell invasion and dissemination to distant sites. uPA, uPAR and the plasminogen activator inhibitor type 1 (PAI-1) are overexpressed in some GOCs. Accumulating evidence points to a causal role of activated receptor tyrosine kinase pathways enhancing uPAS expression in GOCs. Expression of these components are associated with poorer clinicopathological features and patient survival. Stromal cells, including tumour-associated macrophages and myofibroblasts, also express the key uPAS proteins, supporting the argument of stromal involvement in GOC progression and adverse effect on patient survival. uPAS proteins can be detected on circulating leucocytes, circulating tumour cells and within the serum; all have the potential to be developed into circulating biomarkers of GOC. Herein, we review the experimental and clinical evidence supporting uPAS expression as clinical biomarker in GOC, with the goal of developing targeted therapeutics against the uPAS.