Regulation of Cell Migration and Invasion by Specific Modules of uPA: Mechanistic Insights and Specific Inhibitors

Abstract

Urokinase (uPA) is a 411 residues serine protease originally identified for its ability to activate plasminogen and generate plasmin, a broad-spectrum matrix- and fibrin-degrading enzyme. Later, this protease has been shown to possess also a clear-cut ability to stimulate cell migration and survival in a catalytic-independent manner. This activity turned out to be exerted through the growth factor-like domain (GFD-like, residues 1-49) of the protease binding to a GPIanchored membrane receptor (uPAR), in complex with transmembrane receptors such as integrins, the epidermal growth factor and the formyl-peptide receptors. Direct binding of uPA to integrins through its kringle (residues 50-131) and connecting peptide (residues 132-158) regions results in enhanced migration. The dual function of uPA in promoting migration while reducing the physical resistance of extracellular matrix underlies its crucial role in the invasion of malignant tumours. Consolidated evidence emerging from animal models and clinical studies shows that the overexpression of uPA is a causal determinant to tumour metastasis and is associated to a poor prognosis. Therefore, pinpointing the molecular interactions and identifying novel agents to interfere with the diverse activities of uPA is a goal of basic and applied research. In this review, we discuss the general theme of cell migration and invasion. A description of the uPA structure-function relationship and the functional effects of isolated domains is presented. Current information on molecular agonistic as well as antagonistic compounds, including the compounds which have reached clinical trials, is provided.

Antibody-based PET of uPA/uPAR signaling with broad applicability for cancer imaging

“…This observation has led to rapid development of anti-cancer therapeutics based on targeting of the uPA/uPAR system [6, 27]. In order to meet this fast pace of therapeutic development, different molecular imaging probes have been designed to visualize uPA/uPAR expression in vivo with more sensitivity and reliability, providing guidance on evaluation of a specific therapeutic.…”

Neutralizing the EGF receptor in glioblastoma cells stimulates cell migration by activating uPAR-initiated cell signaling

“…uPAR promotes cell migration by two major mechanisms. 23 , 57 By binding and promoting activation of uPA as a protease at the cancer cell surface, uPAR assembles a cell-surface protease system, which may aid in the degradation of tissue boundaries for the migrating cancer cell. 22 , 57 – 59 , 64 uPAR also promotes cell migration by its effects on pro-migratory cell-signaling factors, such as Rac1 and ERK1/2.…”

Antimetastatic Effect by Targeting CTC Cluster—Response

“…Thus, we agree with the concerns of Dr. Soria and colleagues that the potential of uPA as risk factor may not be ruled out. The other reports consistently support a cancer promoting role of uPA and chemical intervention on uPA is expected as cancer therapeutic method (2,3). In our experimental condition, it is likely that CTC cluster-dissociating potential of uPA was dominant over its disease-driving effect due to extremely rapid metastasis.…”