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

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.

Keywords: gastrointestinal neoplasms; stomach neoplasms; urokinase plasminogen activator; urokinase-type plasminogen activator.

Figure 1. The uPA system

Schematic representation of the urokinase plasminogen activation (uPA) system. The membrane bound urokinase receptor (uPAR) binds circulating inactive pro-uPA, facilitating the activation of pro-uPA to uPA which subsequently converts co-localised plasminogen to plasmin that can directly degrade components of the extracellular matrix (ECM) and activate pro-matrix metalloproteases (MMP) to further break down ECM. Plasminogen activator inhibitors 1 or 2 (PAI-1, PAI-2) are efficient endogenous inhibitors of uPA.

Figure 2. Study selection flow diagram

HR –hazard ratio; OS–overall survival; RFS–recurrence free survival.

Figure 3. Risk of bias summary

For each bias domain: green = “low risk” means that sufficient data was available to allow assessment of quality and fulfilled criteria for each domain, and accordingly is deemed low risk of bias. Orange = “unclear risk” means that insufficient data was presented to adequately assess the quality of the domain and accordingly the study has potentially high risk of bias. There were no studies deemed high risk of bias.

Figure 4. Pooled estimate of hazard ratio (HR) for uPA expression and overall survival (OS)

Pooled estimate of hazard ratio (HR) for overall survival. The square on each bar represents the HR for an individual trial, and the bar shows the 95% confidence interval (CI). The diamond represents a pooled estimate with the centre of the diamond giving the HR estimate, and the extremes of the diamond representing the 95% CI. 24.

Figure 5. Pooled estimate of hazard ratio (HR) for uPAR expression and overall survival (OS)

Figure 6. Pooled estimate of hazard ratio (HR) for PAI-1 expression and overall survival (OS)