Therapeutic targeting of tumor growth and angiogenesis with a novel anti-S100A4 monoclonal antibody

• Published in: PloS one Vol. 8; no. 9; p. e72480
• Main Authors: Hernández, Jose Luis, Padilla, Laura, Dakhel, Sheila, Coll, Toni, Hervas, Rosa, Adan, Jaume, Masa, Marc, Mitjans, Francesc, Martinez, Josep Maria, Coma, Silvia, Rodríguez, Laura, Noé, Véronique, Ciudad, Carlos J, Blasco, Francesc, Messeguer, Ramon
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04-09-2013; Public Library of Science (PLoS)
• Subjects: Analysis; Angiogenesis; Angiogènesi; Animal models; Animals; Antibodies, Monoclonal - therapeutic use; Anticossos monoclonals; Antineoplastic Agents - therapeutic use; Biochemistry; Biology; Blood proteins; Blotting, Western; Breast cancer; Calcium; Calcium-binding protein; Cancer; Cell cycle; Cell growth; Cell Line, Tumor; Cell migration; Càncer; Electrophoretic Mobility Shift Assay; Endothelial cells; Enzyme-Linked Immunosorbent Assay; Esophagus; Ethics; Female; Fibroblasts; Gelatinase B; Gene Expression Regulation, Neoplastic - drug effects; Growth; Health aspects; Human Umbilical Vein Endothelial Cells; Humans; Immunodeficiency; Immunohistochemistry; Laboratories; Medical prognosis; Medicine; Melanoma; Metastasis; Mice; Mice, Nude; Molecular biology; Monoclonal antibodies; Motility; Neovascularization; Neovascularization, Pathologic - drug therapy; Pancreas; Pharmacy; Prostate; Protein binding; Proteins; Proteïnes de la sang; Real-Time Polymerase Chain Reaction; S100 Calcium-Binding Protein A4; S100 Proteins - antagonists & inhibitors; S100 Proteins - immunology; S100A4 protein; Stromal cells; Studies; Surface Plasmon Resonance; Therapeutic targets; Tumorigenesis; Tumors; Vascular endothelial growth factor; Vascularization; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0072480

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.