Experimental and Clinical Evidence Supports the Use of Urokinase Plasminogen Activation System Components as Clinically Relevant Biomarkers in Gastroesophageal Adenocarcinoma

Abstract

Gastric and oesophageal cancers (GOCs) are lethal cancers which metastasise early and recur frequently, even after definitive surgery. The urokinase plasminogen activator system (uPAS) is strongly implicated in the invasion and metastasis of many aggressive tumours including GOCs. Urokinase plasminogen activator (uPA) interaction with its receptor, urokinase plasminogen activator receptor (uPAR), leads to proteolytic activation of plasminogen to plasmin, a broad-spectrum protease which enables tumour cell invasion and dissemination to distant sites. uPA, uPAR and the plasminogen activator inhibitor type 1 (PAI-1) are overexpressed in some GOCs. Accumulating evidence points to a causal role of activated receptor tyrosine kinase pathways enhancing uPAS expression in GOCs. Expression of these components are associated with poorer clinicopathological features and patient survival. Stromal cells, including tumour-associated macrophages and myofibroblasts, also express the key uPAS proteins, supporting the argument of stromal involvement in GOC progression and adverse effect on patient survival. uPAS proteins can be detected on circulating leucocytes, circulating tumour cells and within the serum; all have the potential to be developed into circulating biomarkers of GOC. Herein, we review the experimental and clinical evidence supporting uPAS expression as clinical biomarker in GOC, with the goal of developing targeted therapeutics against the uPAS.

Keywords: biomarkers; circulating tumour cell (CTC); gastric cancer; oesophageal cancer; plasminogen activator inhibitor type 1 (PAI-1); serine proteases; serpins; tumour microenvironment; urokinase plasminogen activator (uPA); urokinase plasminogen activator receptor (uPAR).

Figure 1

Overview of the urokinase plasminogen activation system. The binding of urokinase plasminogen activator (uPA) to its receptor, urokinase plasminogen activator receptor (uPAR) and generation of cell surface localised plasmin (which is protected from inhibition by α2-antiplasmin) instigates multiple extracellular and intracellular (signaling) effects resulting in tissue remodeling and cellular proliferation, cell survival as well as altered cellular adhesion and migration. In cancer, uPAS components including uPA, uPAR and plasminogen activator inhibitor-1 (PAI-1) are upregulated in an uncontrolled fashion and contribute to inappropriate cell signaling and proteolysis. Upregulators of the plasminogen activation system include, but are not limited to, the Epidermal Growth Factor (EGF), Hepatocyte Growth Factor (HGF), Prostaglandin-E2 (PGE-2) and Tumour Growth Factor-beta (TGF-β). See text for details. Created with BioRender.com (accessed on 17 June 2021).

Figure 2

Kaplan-Meier curve showing association of GOC tumour uPAR score and overall survival (OS). Low uPAR (0–1) and high uPAR expression (>2) on tumour cells assessed by immunohistochemistry (IHC) at (a) tumour invasion front (n = 43; p = 0.02) and (b) tumour core (n = 24; p = 0.2).

Figure 3

Tissue expression of uPAR is increased in patients where more than 60% of their epithelial cell adhesion molecule (EpCAM) selected circulating tumour cells (CTCs) co-expressed uPAR. Mean score in the lower group 1.3, higher group 3.3 (n = 18, p = 0.0008).

Figure 4

Kaplan Meier curves showing OS demonstrating (n = 43): (a) a trend of improved survival seen in patients with less than 10 EpCAM+/uPAR+ CTCs (p = 0.06); (b) no survival benefit seen where more than 60% of EpCAM+ CTCs also co-expressed uPAR (p = 0.5).