Abstract
Simple SummaryThe uPA/uPAR system is highly involved in cancer progression and metastasis. Many studies have definitively assessed that the high expression of urokinase-type plasminogen activator (uPA) and membrane urokinase-type plasminogen activator receptor (uPAR) in patients does correlate with metastasis formation and poor prognosis. Thus, due to the key role of uPA and uPAR in cancer, it is essential to develop compounds able to interfere with and/or inhibit their activity. In this review, we discuss the role of uPA and uPAR as diagnostic, prognostic and therapeutic markers in tumors. Moreover, we describe, in-depth, the design, construction and analysis of uPA and uPAR inhibitors in in vitro and in vivo models. Clinical trials, testing some of these inhibitors, are also accurately described.Several studies have ascertained that uPA and uPAR do participate in tumor progression and metastasis and are involved in cell adhesion, migration, invasion and survival, as well as angiogenesis. Increased levels of uPA and uPAR in tumor tissues, stroma and biological fluids correlate with adverse clinic–pathologic features and poor patient outcomes. After binding to uPAR, uPA activates plasminogen to plasmin, a broad-spectrum matrix- and fibrin-degrading enzyme able to facilitate tumor cell invasion and dissemination to distant sites. Moreover, uPAR activated by uPA regulates most cancer cell activities by interacting with a broad range of cell membrane receptors. These findings make uPA and uPAR not only promising diagnostic and prognostic markers but also attractive targets for developing anticancer therapies. In this review, we debate the uPA/uPAR structure–function relationship as well as give an update on the molecules that interfere with or inhibit uPA/uPAR functions. Additionally, the possible clinical development of these compounds is discussed.
Highlights
Metastases are often the cause of cancer patient deaths
We found that the residue Ser90, located in the chemotactic uPAR84–95 sequence influences the conformation of the nearby residues and that the substitution of Ser90 with a glutamic acid residue in the membrane-associated uPAR, prevents agonist-triggered Formyl-peptide receptors type 1 (FPR1) activation and internalization, and interferes with uPAR/FPR1/Vn receptors (VnR) crosstalk, blocking cell migration and invasion, both in vitro and in vivo [132]
Even though some of them are very effective in preclinical studies and animal models [12], few clinical trials including uPAR inhibitors has been accomplished, until now, whereas only a few clinical studies have been conducted, using urokinase-type plasminogen activator (uPA) inhibitors (Table 1)
Summary
Metastases are often the cause of cancer patient deaths. Unlike therapies targeting primary tumors, those targeting tumor metastases have only minimally improved. UPA and uPAR have been regarded as diagnostic and prognostic markers in cancer, and high levels of both uPA and uPAR in tissue and serum have been demonstrated to correlate with a poor patient outcome in different types of primary as well as metastatic malignancies [8,11,12,13,14,15,16] In this regard, Kjaer and colleagues are developing highly specific peptide-based ligands for positron emission tomography (PET) imaging, targeting uPAR in an effort to design clinical trials for cancer patients [17]. Inhibitors of uPA have been constructed, interfering with either uPA catalytic activity or uPA-dependent signaling
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