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

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.

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“…A systematic review of nine studies reported a pooled expression of 25% (146 of 573 patients) for HER-2 in EAC, but this meta-analysis revealed large differences in results between studies [19]. The pooled expression of uPAR was reported as 57% (range 14-90) for 12 gastroesophageal cancer studies [20], which is considerably higher than the 15% in our results. This may be explained by the random selection of tumor tissue.…”

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“…Another key gene "PLAU" gene located on 10q22.2 encodes urokinase type plasminogen activator (uPA), transforming plasminogen into plasminogen. 29 And previous studies have shown that uPA protein is mainly located in the cytoplasm, and both ectopic and eutopic endometrium express uPA protein, 30 which is positively expressed in vascular endothelial cells. 31 It is involved in the occurrence and development of endometriosis.…”

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“…In addition, it plays an important role in cancer progression and metastasis. In addition, expression pattern, secretion, and function of uPA members have been observed in a broad range of human malignancies [6,7]. A number of investigations have indicated that uPA, uPAR, and PAI-1 are elevated in hepatocellular carcinoma (HCC) in comparison to normal liver tissues [22,23].…”

“…In addition, it plays an important role in cancer progression and metastasis. In addition, expression pattern, secretion, and function of uPA members have been observed in a broad range of human malignancies [6,7].…”