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      Changes in the expression and subcellular distribution of galectin-3 in clear cell renal cell carcinoma

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          Abstract

          Background

          Clear cell renal cell carcinoma, a solid growing tumor, is the most common tumor in human kidney. Evaluating the usefulness of β-galactoside binding galectin-3 as a diagnostic marker for this type of cancer could open avenues for preventive and therapeutic strategies by employing specific inhibitors of the lectin. To study a putative correlation between the extent of galectin-3 and the development of clear cell renal cell carcinoma, we monitored the quantity and distribution of this lectin in tissue samples from 39 patients.

          Methods

          Galectin-3 concentrations in normal, intermediate and tumor tissues were examined by immunofluorescence microscopy and on immunoblots with antibodies directed against galectin-3 and renal control proteins. The cell nuclei were isolated to determine quantities of galectin-3 that were transferred into this compartment in normal or tumor samples.

          Results

          Immunofluorescence data revealed a mosaic pattern of galectin-3 expression in collecting ducts and distal tubules of normal kidney. Galectin-3 expression was significantly increased in 79% of tumor samples as compared to normal tissues. Furthermore, we observed an increase in nuclear translocation of the lectin in tumor tissues.

          Conclusions

          Our data indicate that changes in the cellular level of galectin-3 correlate with the development of clear cell renal cell carcinoma, which is in line with previously published data on this specific type of tumor. In most of these studies the lectin tends to be highly expressed in tumor tissues. Furthermore, this study suggests that the increase in the proportion of galectin-3 affects the balance from a cytosolic distribution towards translocation into the nucleus.

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          Most cited references34

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          Galectins as modulators of tumour progression.

          Galectins are a family of animal lectins with diverse biological activities. They function both extracellularly, by interacting with cell-surface and extracellular matrix glycoproteins and glycolipids, and intracellularly, by interacting with cytoplasmic and nuclear proteins to modulate signalling pathways. Current research indicates that galectins have important roles in cancer; they contribute to neoplastic transformation, tumour cell survival, angiogenesis and tumour metastasis. They can modulate the immune and inflammatory responses and might have a key role helping tumours to escape immune surveillance. How do the different members of the Galectin family contribute to these diverse aspects of tumour biology?
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            Intravascular metastatic cancer cell homotypic aggregation at the sites of primary attachment to the endothelium.

            The two major theories of cancer metastasis, the seed and soil hypothesis and the mechanical trapping theory, view tumor cell adhesion to blood vessel endothelia and cancer cell aggregation as corresponding key components of the metastatic process. Here, we demonstrate in vitro, ex vivo, and in vivo that metastatic breast and prostate carcinoma cells form multicellular homotypic aggregates at the sites of their primary attachment to the endothelium. Our results suggest that metastatic cell heterotypic adhesion to the microvascular endothelium and homotypic aggregation represent two coordinated subsequent steps of the metastatic cascade mediated largely by similar molecular mechanisms, specifically by interactions of tumor-associated Thomsen-Friedenreich glycoantigen with the beta-galactoside-binding protein, galectin-3. In addition to inhibiting neoplastic cell adhesion to the endothelium and homotypic aggregation, disrupting this line of intercellular communication using synthetic Thomsen-Friedenreich antigen masking and Thomsen-Friedenreich antigen mimicking compounds greatly affects cancer cell clonogenic survival and growth as well. Thus, beta-galactoside-mediated intravascular heterotypic and homotypic tumor cell adhesive interactions at the sites of a primary attachment to the microvascular endothelium could play an important role during early stages of hematogenous cancer metastasis.
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              Galectin-3 increases gastric cancer cell motility by up-regulating fascin-1 expression.

              Galectin-3 is a beta-galactoside-binding protein that increases gastric cancer cell motility in response to integrin signaling and is highly expressed in gastric tumor cells. Galectin-3 induces cytoskeletal remodeling to increase cell motility, but the mechanisms of this process are not understood. We investigated the effects of galectin-3 on fascin-1, an actin-bundling protein. We collected malignant and normal tissues from gastric cancer patients and examined the expression levels of galectin-3 and fascin-1. We silenced galectin-3 expression in human gastric cancer cell lines using small interfering RNA and lenti-viral constructs and determined the effects on fascin-1 expression, cell motility, and invasion. Malignant gastric tissues expressed high levels of galectin-3 and fascin-1, compared with normal gastric tissues. Silencing of galectin-3 resulted in altered cancer cell morphology, reduced fascin-1 expression, decreased cell motility, and reduced malignant cell invasion. Galectin-3 overexpression reversed these effects. Silencing of fascin-1 also reduced cell motility and caused changes in cell shape, as did silencing of galectin-3. Furthermore, galectin-3 silencing inhibited the interaction between glycogen synthase kinase (GSK)-3beta, beta-catenin, and T-cell factor (TCF) 4, and the binding of beta-catenin/TCF-4 to the fascin-1 promoter. Nuclear localization of GSK-3beta and beta-catenin were not detected when galectin-3 was silenced. Overexpression of mutated galectin-3 (with mutations in the GSK-3beta binding and phosphorylation motifs) did not increase fascin-1 levels, in contrast to overexpression of wild-type galectin-3. Galectin-3 increases cell motility by up-regulating fascin-1 expression. Galectin-3 might be a potential therapeutic target for the prevention and treatment of gastric cancer progression. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                J Exp Clin Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central
                0392-9078
                1756-9966
                2011
                29 September 2011
                : 30
                : 1
                : 89
                Affiliations
                [1 ]Department of Cell Biology and Cell Pathology, Philipps University of Marburg, Robert-Koch-Str.6, 35037 Marburg, Germany
                [2 ]Department of Urology and Pediatric Urology, University Medical Center Marburg, Baldinger Strasse, 35033 Marburg, Germany
                [3 ]Institut Jacques-Monod, CNRS UMR 7592, Université Paris 7, Bâtiment Buffon, 15 Rue Hélène Brion, 75013 Paris, France
                Article
                1756-9966-30-89
                10.1186/1756-9966-30-89
                3220637
                21958686
                4da2e44a-5620-4e21-94bb-7143bef88b74
                Copyright ©2011 Straube et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 31 August 2011
                : 29 September 2011
                Categories
                Research

                Oncology & Radiotherapy
                clear cell renal cell carcinoma,nuclear translocation,galectin-3,tumorigenesis

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