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.

Cancer Progression Gene Expression Profiling Identifies the Urokinase Plasminogen Activator Receptor as a Biomarker of Metastasis in Cutaneous Squamous Cell Carcinoma

“…VEGFA (vascular endothelial growth factor A) and EGF (epidermal growth factor) are predicted to be significantly activated master regulators driving differential gene expression in MET vs. PRI- ( Supplementary Data Sheet 6 ). Both growth factors are known stimulators of uPAR mRNA expression ( 23 ). Figure 4B demonstrates the VEGFA-mediated upregulation of genes involved in ECM interaction and MMP remodeling (also TSK-specific genes ( 9 )) such as MMP1 , MMP10 , MMP12 , PLAU , and CXCL10 in MET, as well as FLT1 (encodes VEGFA receptor), which in turn promote metastatic functions such as angiogenesis, growth, migration and invasion, and evasion of apoptosis.…”

“…Interestingly, SERPINE1 (encodes plasminogen activator inhibitor type 1, a potent inhibitor of uPAR-bound uPA) was also upregulated in all our tumor cohorts (refer to Supplementary Data Sheet 2 ). This is of note because combined upregulated PLAU and SERPINE1 expression is strongly associated with poor cancer outcomes in various other cancers via mechanisms that affect cell adhesion, ECM remodeling, and signaling pathways leading to increased cell survival, migration, invasion, and angiogenesis ( 21 , 23 , 70 – 73 ).…”

“…Altered proteolysis and EMT programs are required for ECM remodeling and tumor cell escape ( 17 – 19 ). In particular, overexpression of the urokinase plasminogen activator (uPA, encoded by PLAU ) and its cognate cell surface receptor (uPAR, encoded by PLAUR ) (including downstream effector and upstream regulator molecules) is associated with EMT ( 20 ) and correlates with increased metastasis and/or poorer patient survival in many solid tumor types ( 21 – 23 ) including mucosal squamous cell carcinoma of the oral cavity ( 24 – 30 ).…”

“…Plasmin and MMPs are also responsible for the release and activation of latent growth/angiogenic factors (such as EGF and VEGF) and chemokines from the ECM, which promotes cellular proliferation, survival, and motility ( 18 , 22 ). Activated receptor tyrosine kinase pathways have also been shown to enhance uPA system expression in cancer ( 23 ).…”

A tEMTing target? Clinical and experimental evidence for epithelial-mesenchymal transition in the progression of cutaneous squamous cell carcinoma (a scoping systematic review)

“…The uPA system is a regulator of MMPs and hence might be an attractive therapeutic target to reduce invasion and metastasis. The upregulation of uPA/ uPAR and SERPINE1 is associated with poor prognosis in multiple cancers including HNSCC and many other solid tumors [ 171 – 174 ]. uPA-uPAR complexes can interact with integrins, vitronectin and LDLR endocytosis receptors as well as induce plasmin-mediated ECM degradation [ 171 – 174 ].…”