UPA/uPAR and SERPINE1 in head and neck cancer: role in tumor resistance, metastasis, prognosis and therapy

Miguel Angel Pavón,Maria Virtudes Céspedes,Ramón Mangues,Isolda Casanova,Irene Arroyo-Solera,Xavier León

doi:10.18632/oncotarget.10344

Abstract

There is strong evidence supporting the role of the plasminogen activator system in head and neck squamous cell carcinoma (HNSCC), particularly of its uPA (urokinase plasminogen activator) / uPAR (urokinase plasminogen activator receptor) and SERPINE1 components. Overexpression of uPA/uPAR and SERPINE1 enhances tumor cell migration and invasion and plays a key role in metastasis development, conferring poor prognosis. The apparent paradox of uPA/uPAR and its inhibitor SERPINE1 producing similar effects is solved by the identification of SERPINE1 activated signaling pathways independent of uPA inhibition. Both uPA/uPAR and SERPINE1 are directly linked to the induction of epithelial-to-mesenchymal transition, the acquisition of stem cell properties and resistance to antitumor agents. The aim of this review is to provide insight on the deregulation of these proteins in all these processes.We also summarize their potential value as prognostic biomarkers or potential drug targets in HNSCC patients. Concomitant overexpression of uPA/uPAR and SERPINE1 is associated with a higher risk of metastasis and could be used to identify patients that would benefit from an adjuvant treatment. In the future, the specific inhibitors of uPA/uPAR and SERPINE1, which are still under development, could be used to design new therapeutic strategies in HNSCCs.

Highlights

Head and neck cancer is the sixth most common cancer in incidence worldwide [1]
The fact that the overexpression of urokinase-type plasminogen (uPA)/ uPAR and its main inhibitor SERPINE1, produce similar effects on cell migration, tumor spread and prognosis may seem contradictory, but several reports suggest that SERPINE1 activates signaling pathways independent of the inhibition of the uPA/uPAR complex
UPA/uPAR and SERPINE1 are closely associated with the induction of epithelialmesenchymal transition (EMT) and the acquisition of cancer stem cell properties, which could contribute to resistance to therapy

Summary

Introduction

Head and neck cancer is the sixth most common cancer in incidence worldwide [1]. More than 500,000 new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed each year (http://globocan.iarc. fr). More than 500,000 new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed each year Two thirds of patients are diagnosed at advanced stages, as lymph node metastases are often the first sign of the disease [2]. Surgery can significantly impact organ function, produce damage to the structures involved in swallowing and speech, and greatly reduce patient quality of life [3]. Multimodal treatments have improved loco-regional disease control and organ preservation in head and neck patients, but five-year survival remains around 50% [2]. A high percentage of patients develop recurrences, metastasis or secondary tumors after treatment, which results in a poor clinical outcome [4,5,6,7,8]

Objectives

Conclusion