The urokinase plasminogen activation (uPA) system is a key pathway in facilitating tumour invasion and establishment of metastases. Although the uPA system is a proven biomarker in various solid tumours, its significance in gastro-oesophageal cancer has not been established. This study aims to evaluate clinicopathological features and prognostic outcomes associated with expression of key components of the uPA system in primary resected oesophageal, gastro-oesophageal junction and gastric adenocarcinomas.
Method: Studies evaluating urokinase plasminogen activator (uPA), urokinase plasminogen activator receptor (uPAR) and plasminogen activator-1 (PAI-1) and 2 (PAI-2) were identified by literature searches. Pooled hazard ratios (HRs) were calculated for overall survival (OS), recurrence free survival (RFS) and clinicopathological correlations including tumour stage, grade, invasion and presence of metastases. Data were synthesised using generic inverse variance and a random effect modelling.
Results: Forty-one studies of 2689 patients were identified. After applying stringent exclusion criteria, twenty-two (1966 patients) were included in the meta-analysis. Expression rates of uPA, uPAR, PAI-1 and PAI-2 were 55.7%, 55.1%, 51.7%, 43.0%, respectively. uPA, uPAR and PAI-1 expression are significantly associated with high risk clinicopathological features. High uPA expression is associated with shorter RFS (HR 1.9 95%CI 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 95%CI 1.07-3.58, p=0.03) and OS (HR 1.84 95%CI 1.28-2.64, p<0.0001).
Conclusion: Gastro-oesophageal cancer is a common and lethal malignancy, currently marked by a lack of predictive biomarkers. We propose that the uPA system is a clinically relevant biomarker in gastro-oesophageal cancers, with high expression of uPA, uPAR and uPA-1 associated with higher risk diseases and poorer outcomes. Further prospective studies are required to confirm the role of uPA, uPAR and uPA-1 as independent prognostic markers.