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      Therapeutic Targeting of Tumor Growth and Angiogenesis with a Novel Anti-S100A4 Monoclonal Antibody

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          Abstract

          S100A4, a member of the S100 calcium-binding protein family secreted by tumor and stromal cells, supports tumorigenesis by stimulating angiogenesis. We demonstrated that S100A4 synergizes with vascular endothelial growth factor (VEGF), via the RAGE receptor, in promoting endothelial cell migration by increasing KDR expression and MMP-9 activity. In vivo overexpression of S100A4 led to a significant increase in tumor growth and vascularization in a human melanoma xenograft M21 model. Conversely, when silencing S100A4 by shRNA technology, a dramatic decrease in tumor development of the pancreatic MiaPACA-2 cell line was observed. Based on these results we developed 5C3, a neutralizing monoclonal antibody against S100A4. This antibody abolished endothelial cell migration, tumor growth and angiogenesis in immunodeficient mouse xenograft models of MiaPACA-2 and M21-S100A4 cells. It is concluded that extracellular S100A4 inhibition is an attractive approach for the treatment of human cancer.

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          RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides.

          M A Hofmann, S. Drury, C Fu … (1999)
          S100/calgranulin polypeptides are present at sites of inflammation, likely released by inflammatory cells targeted to such loci by a range of environmental cues. We report here that receptor for AGE (RAGE) is a central cell surface receptor for EN-RAGE (extracellular newly identified RAGE-binding protein) and related members of the S100/calgranulin superfamily. Interaction of EN-RAGEs with cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflammatory mediators. Blockade of EN-RAGE/RAGE quenches delayed-type hypersensitivity and inflammatory colitis in murine models by arresting activation of central signaling pathways and expression of inflammatory gene mediators. These data highlight a novel paradigm in inflammation and identify roles for EN-RAGEs and RAGE in chronic cellular activation and tissue injury.
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            Intracellular and extracellular roles of S100 proteins.

            Rosario Donato (2003)
            S100, a multigenic family of non-ubiquitous Ca(2+)-modulated proteins of the EF-hand type expressed in vertebrates exclusively, has been implicated in intracellular and extracellular regulatory activities. Members of this protein family have been shown to interact with several effector proteins within cells thereby regulating enzyme activities, the dynamics of cytoskeleton constituents, cell growth and differentiation, and Ca(2+) homeostasis. Structural information indicates that most of S100 proteins exist in the form of antiparallelly packed homodimers (in some cases heterodimers), capable of functionally crossbridging two homologous or heterologous target proteins in a Ca(2+)-dependent (and, in some instances, Ca(2+)-independent) manner. In addition, extracellular roles have been described for several S100 members, although secretion (via an unknown mechanism) has been documented for a few of them. Extracellular S100 proteins have been shown to exert regulatory effects on inflammatory cells, neurons, astrocytes, microglia, and endothelial and epithelial cells, and a cell surface receptor, RAGE, has been identified as a potential S100A12 and S100B receptor transducing the effects of these two proteins on inflammatory cells and neurons. Other cell surface molecules with ability to interact with S100 members have been identified, suggesting that RAGE might not be a universal S100 protein receptor and/or that a single S100 protein might interact with more than one receptor. Collectively, these data indicate that members of the S100 protein family are multifunctional proteins implicated in the regulation of a variety of cellular activities. Copyright 2003 Wiley-Liss, Inc.
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              Binding of S100 proteins to RAGE: an update.

              Estelle Leclerc, Günter Fritz, Stefan Vetter … (2009)
              The Receptor for Advanced Glycation Endproducts (RAGE) is a multi-ligand receptor of the immunoglobulin family. RAGE interacts with structurally different ligands probably through the oligomerization of the receptor on the cell surface. However, the exact mechanism is unknown. Among RAGE ligands are members of the S100 protein family. S100 proteins are small calcium binding proteins with high structural homology. Several members of the family have been shown to interact with RAGE in vitro or in cell-based assays. Interestingly, many RAGE ligands appear to interact with distinct domains of the extracellular portion of RAGE and to trigger various cellular effects. In this review, we summarize the modes of S100 protein-RAGE interaction with regard to their cellular functions.
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                Author and article information

                Contributors
                Sujit Basu: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 4 September 2013
                Volume: 8
                Issue: 9
                Electronic Location Identifier: e72480
                Affiliations
                [1 ]Biomed Division, LEITAT Technological Center, Barcelona, Spain
                [2 ]Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Barcelona, Spain
                [3 ]Project Area of Biopol’H, L’Hospitalet de Llobregat, Spain
                Ohio State University, United States of America
                Author notes

                Competing Interests: J.L. Hernández, L. Padilla, S. Dakhel, T. Coll, R. Hervas, J. Adan, M. Masa, F. Mitjans, J.M. Martinez, R. Messeguer are holders of patent WO/2011/157724: “S100A4 antibodies and therapeutic uses thereof”. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: JLH FB RM CJC. Performed the experiments: JLH LP SD TC JMM SC LR. Analyzed the data: JLH RM FB. Contributed reagents/materials/analysis tools: RH JA MM VN FM. Wrote the paper: JLH RM FB CJC VN.

                Article
                Publisher ID: PONE-D-13-09563
                DOI: 10.1371/journal.pone.0072480
                PMC ID: 3762817
                PubMed ID: 24023743
                SO-VID: c45d4af4-de36-4d0f-a5fd-b63860ce8b9c
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 7 March 2013
                Date accepted : 10 July 2013
                Page count
                Pages: 17
                Funding
                The work was supported by Grants from ACC1Ó, the Catalan Business Competitiveness Support Agency and SAF08-043/SAF2011-23582 from “Plan Nacional de Investigación Científica” (Spain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Mouse
                Subject: Medicine
                Subject: Clinical Research Design
                Subject: Animal Models of Disease
                Subject: Dermatology
                Subject: Skin Neoplasms
                Subject: Malignant Skin Neoplasms
                Subject: Melanomas
                Subject: Oncology
                Subject: Cancer Treatment
                Subject: Antiangiogenesis Therapy
                Subject: Antibody Therapy
                Subject: Basic Cancer Research
                Subject: Cancer Detection and Diagnosis

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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