Inhibition of the invasion capacity of carcinoma cells by WX‐UK1, a novel synthetic inhibitor of the urokinase‐type plasminogen activator system

Abstract

The overall survival rate of patients suffering from carcinomas has remained poor and nearly unchanged over the last decades. This is mainly due to the so-called minimal residual disease, i.e., remaining tumor cells that overcome surgery and/or radiotherapy and are the cause of locoregional and distant metastases. To metastasize, tumor cells take advantage of proteases to invade and remodel surrounding tissues. Here, we analyzed the efficiency of WX-UK1, a novel 3-amidinophenylalanine-based inhibitor of the uPA system, at inhibiting the invasive capacity of carcinoma cells. First, uPAR expression was characterized in different carcinoma cell lines, including SCCHN, breast and cervical carcinoma. Thereafter, the invasive potential of these cell lines was determined using Matrigel invasion chambers and a spheroid cocultivation model with human fibroblasts. uPAR expression levels correlated positively with invasion capacity, which could be significantly inhibited by WX-UK1. Despite improvements in surgical and radiotherapeutic techniques, the 5-year survival rate of patients suffering from SCCHN has remained poor and nearly unchanged over the last decades, primarily due to their tendency to develop locoregional and distant metastases. 1 This underlines the necessity of new modalities to treat MRD, 2 i.e., the spread of occult malignant cells to locoregional and/or distant sites and inhibition of metastasis formation. Both MRD and metastasis formation are major causes of recurrence and therefore death in cancer patients.Tumor invasion and metastasis formation are complex biologic processes depending on matrix-degrading proteolytic systems that allow tumor cells to detach from their primary site; migrate through the surrounding tissue, blood or lymph vessels; and distribute to distant sites. 3 One of the major proteolytic systems involved in these processes is the urokinase-type plasminogen activation system with its key components: uPA, the cell-surface receptor uPAR (CD87) and the inhibitor PAI-1. 4,5 Plasmin, generated from its precursor plasminogen by activators such as uPA, catalyzes the degradation of extracellular matrix components and is important for fibrinolysis. Proteases such as plasmin and others increase the invasion capacity and tissue-remodeling ability of carcinoma cells. 6 Upon binding to its receptor on the surface of various cell types, the activator can induce direct plasmin-mediated proteolysis or indirect activation of other proteinases, like metalloproteases, by triggering signal-transduction pathways and thereby facilitate matrix degradation and tumor invasion. 6 uPA can also be activated by cysteine proteases like cathepsin B or L, which are located intracellularly and at tumor cell surfaces. 7 Additionally, components of the uPA system are overexpressed in malignant tumors such as breast, gastric, esophageal, lung, prostate, colorectal and others, 8 correlating with a poor prognosis. High levels of uPA components were also measured in head-and-neck carcinomas and can be used as a prognostic...

Enhanced Expression of Rab27A Gene by Breast Cancer Cells Promoting Invasiveness and the Metastasis Potential by Secretion of Insulin-Like Growth Factor-II

“…Kwon et al (49) observed that IGF-II mediated VEGF expression by the tyrosine kinase -Srcextracellular signal-regulated kinase 1/2 pathway and the phosphatidylinositol 3-kinase pathway in human keratinocytes. In addition, previous studies have shown that up-regulated expression of uPA, uPA receptor, and cathepsin D are associated with increased tumor cell invasion and metastasis in several malignancies, including breast cancer (50,51). In our study, we found that MMP-9, VEGF, uPA, and cathepsin D expression, which can be up-regulated by IGF-II overexpression (52,53), were positively modulated by Rab27A in MDA-MB-231 and MDA-MB-435 cells; however, no significantly different expression in TIMP-1, TIMP-2, MMP-1, MMP-2, basic fibroblast growth factor, and uPA receptor was observed.…”

Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-κB-dependent activation of the urokinase plasminogen activator system

“…A number of experimental and clinical studies highlight the significance of the u-PA system in colorectal cancer abound (Ertongur et al, 2004;Setyono-Han et al, 2005). Both Harvey et al (1999) and Skelly et al (1997) demonstrated superior 5-year survival rates in patients whose tumour had lower total u-PA expression after curative colon cancer resection.…”

New Antithrombotic Drugs

“…Both Mesupron and WX-UK1 reduce tumor growth and metastasis in vitro and in various animal models. 174,175 A phase 1 study in 19 patients with advanced head and neck cancer revealed a dose-dependent increase in plasma levels of WX-671, and WX-671 was found in tissue samples collected after tumor resection, 176 suggesting that amounts of drug suffi cient to inhibit u-PA are concentrated in the tumor. 176 In a phase 2 study, 95 patients with locally advanced, metastatic pancreatic cancer received either Mesupron (at doses corresponding to 200 or 400 mg of WX-UK1) or placebo in conjunction with weekly gemcitabine.…”