title: Therapeutic targeting of tumor growth and angiogenesis with a novel anti-S100A4 monoclonal antibody.
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.
authors.affiliation: Biomed Division, LEITAT Technological Center, Barcelona, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Hernández
authors.forename: Laura
authors.initials: L
authors.lastname: Padilla
authors.forename: Sheila
authors.initials: S
authors.lastname: Dakhel
authors.forename: Toni
authors.initials: T
authors.lastname: Coll
authors.forename: Rosa
authors.initials: R
authors.lastname: Hervas
authors.forename: Jaume
authors.initials: J
authors.lastname: Adan
authors.forename: Marc
authors.initials: M
authors.lastname: Masa
authors.forename: Francesc
authors.initials: F
authors.lastname: Mitjans
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Martinez
authors.forename: Silvia
authors.initials: S
authors.lastname: Coma
authors.forename: Laura
authors.initials: L
authors.lastname: Rodríguez
authors.forename: Véronique
authors.initials: V
authors.lastname: Noé
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Ciudad
authors.forename: Francesc
authors.initials: F
authors.lastname: Blasco
authors.forename: Ramon
authors.initials: R
authors.lastname: Messeguer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D060888:Real-Time Polymerase Chain Reaction; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D020349:Surface Plasmon Resonance; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human
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