The urokinase plasminogen activation system in gastroesophageal cancer: A systematic review and meta-analysis
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Daniel Brungs1,2,3,4, Julia Chen5, Morteza Aghmesheh1,3,4, Kara L. Vine1,2,4, Therese M. Becker4,6,7,8, Martin G. Carolan1,3,4, Marie Ranson1,2,4
1Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia
2School of Biological Sciences, University of Wollongong, Wollongong, Australia
3Illawarra Cancer Centre, Wollongong Hospital, Wollongong, Australia
4CONCERT-Translational Cancer Research Centre, New South Wales, Australia
5St George Cancer Centre, St George Hospital, Sydney, Australia
6Ingham Institute for Applied Medical Research, Liverpool Hospital, Australia
7School of Medicine, University of Western Sydney, Liverpool, Australia
8South Western Medical School, University of New South Wales, Liverpool, Australia
Daniel Brungs, email: [email protected]
Keywords: stomach neoplasms, gastrointestinal neoplasms, urokinase-type plasminogen activator, urokinase plasminogen activator
Received: November 30, 2016 Accepted: February 07, 2017 Published: February 18, 2017
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.
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