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

• DOI: 10.1371/journal.pone.0072480
• Publication Date: 2013-09-04T21:09:32Z
• Authors: Jose Luis Hernández; Laura Padilla; Sheila Dakhel; Toni Coll; Rosa Hervas; Jaume Adan; Marc Masa; Francesc Mitjans; Josep Maria Martinez; Silvia Coma; Laura Rodríguez; Véronique Noé; Carlos J. Ciudad; Francesc Blasco; Ramon Messeguer
• Keywords: 0301 basic medicine; Science; Blotting, Western; Mice, Nude; Antineoplastic Agents; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Real-Time Polymerase Chain Reaction; Mice; 03 medical and health sciences; Cell Line, Tumor; Human Umbilical Vein Endothelial Cells; Animals; Humans; S100 Calcium-Binding Protein A4; Càncer; Neovascularization; Cancer; Neovascularization, Pathologic; Blood proteins; Q; S100 Proteins; R; Antibodies, Monoclonal; Surface Plasmon Resonance; Immunohistochemistry; Xenograft Model Antitumor Assays; Angiogènesi; 3. Good health; Gene Expression Regulation, Neoplastic; Proteïnes de la sang; Medicine; Monoclonal antibodies; Female; Anticossos monoclonals; Research Article

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.