The urokinase plasminogen activation system in gastroesophageal cancer: A systematic review and meta-analysis

// Daniel Brungs 1, 2, 3, 4 , Julia Chen 5 , Morteza Aghmesheh 1, 3, 4 , Kara L. Vine 1, 2, 4 , Therese M. Becker 4, 6, 7, 8 , Martin G. Carolan 1, 3, 4 , Marie Ranson 1, 2, 4 1 Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia 2 School of Biological Sciences, University of Wollongong, Wollongong, Australia 3 Illawarra Cancer Centre, Wollongong Hospital, Wollongong, Australia 4 CONCERT-Translational Cancer Research Centre, New South Wales, Australia 5 St George Cancer Centre, St George Hospital, Sydney, Australia 6 Ingham Institute for Applied Medical Research, Liverpool Hospital, Australia 7 School of Medicine, University of Western Sydney, Liverpool, Australia 8 South Western Medical School, University of New South Wales, Liverpool, Australia Correspondence to: Daniel Brungs, email: Daniel.brungs@health.nsw.gov.au Keywords: stomach neoplasms, gastrointestinal neoplasms, urokinase-type plasminogen activator, urokinase plasminogen activator Received: November 30, 2016 Accepted: February 07, 2017 Published: February 18, 2017 ABSTRACT Background: The urokinase plasminogen activation (uPA) system is a crucial pathway for tumour invasion and establishment of metastasis. Although there is good evidence that uPA system expression is a clinically relevant biomarker in some solid tumours, its role in gastroesophageal cancer is uncertain. Results: We identified 22 studies encompassing 1966 patients which fulfilled the inclusion criteria. uPA, uPAR, or PAI-1 expression is significantly associated with high risk clinicopathological features. High uPA expression is associated with a shorter RFS (HR 1.90 95% 1.16–3.11, p = 0.01) and OS (HR 2.21 95% CI 1.74–2.80, p < 0.0001). High uPAR expression is associated with poorer OS (HR 2.21 95%CI 1.82–2.69, p < 0.0001). High PAI-1 expression is associated with shorter RFS (HR 1.96 96% CI 1.07–3.58, p = 0.03) and OS (HR 1.84 95%CI 1.28–2.64, p < 0.0001). There was no significant association between PAI-2 expression and OS (HR 0.97 95%CI 0.48–1.94, p < 0.92) although data was limited. Materials and Methods: We undertook a systematic review evaluating expression of uPA, urokinase plasminogen activator receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1/SerpinE1) and plasminogen activator inhibitor-2 (PAI-2/SerpinB2) on primary oesophageal, gastro-oesophageal junction, and gastric adenocarcinomas. We performed a meta-analysis of clinicopathological associations, overall survival (OS) and recurrence free survival (RFS). Conclusions: We conclude that the uPA system is a clinically relevant biomarker in primary gastroesophageal cancer, with higher expression of uPA, uPAR and PAI-1 associated with higher risk disease and poorer prognosis. This also highlights the potential utility of the uPA system as a therapeutic target for improved treatment strategies.