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Abstract
BackgroundThe 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.ResultsWe 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 MethodsWe 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).ConclusionsWe 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.
Highlights
Gastroesophageal cancer is a common and lethal malignancy, marked by modest response to systemic therapies [1]
High urokinase plasminogen activation (uPA) expression is associated with a shorter recurrence free survival (RFS) (HR 1.90 95% 1.16–3.11, p = 0.01) and overall survival (OS) (HR 2.21 95% confidence interval (CI) 1.74–2.80, p < 0.0001)
High urokinase plasminogen activator receptor (uPAR) expression is associated with poorer OS (HR 2.21 95%CI 1.82–2.69, p < 0.0001)
Summary
Gastroesophageal cancer is a common and lethal malignancy, marked by modest response to systemic therapies [1]. A deeper understanding of molecular events characterising carcinogenesis, invasion, progression and metastasis is central for the development of novel therapies. A key process in the development and progression of cancer, including establishment of metastatic disease, is the invasion of malignant cells into normal tissue. The uPA system has a defined role in tissue degradation and extravascular fibrinolysis, and is responsible for most of the activated plasminogen associated with cancer invasion and metastasis [2, 3] (Figure 1). The urokinase plasminogen activation (uPA) system is a crucial pathway for tumour invasion and establishment of metastasis. There is good evidence that uPA system expression is a clinically relevant biomarker in some solid tumours, its role in gastroesophageal cancer is uncertain
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