title: Targeting soluble CD146 with a neutralizing antibody inhibits vascularization, growth and survival of CD146-positive tumors.
abstract: CD146 (MUC-18, MCAM) expression on cancer cells correlates with cancer progression and a bad prognosis in several tumors, including melanoma and pancreatic tumors. Deciphering the mechanism mediating the CD146 role in cancer is essential for generating new therapeutic strategies. We found that CD146 expression in cancer cells is associated with a secretion of soluble CD146 (sCD146) that constitutes an active player in tumor development. Indeed, sCD146 induces the overexpression of its binding protein, angiomotin, on both endothelial and cancer cells and promotes both paracrine effects on angiogenesis and autocrine effects on cancer cells proliferation and survival. These last effects are mediated in part through the induction and phosphorylation of c-myc in cancer cells. In mice models xenografted with human CD146-positive melanoma or pancreatic cancer cells, administration of a novel monoclonal antibody specifically targeting sCD146, but not its membrane form, successfully suppresses tumor vascularization and growth. Our findings demonstrate that sCD146 secreted by CD146-positive tumors mediates important pro-angiogenic and pro-tumoral effects. Targeting sCD146 with a novel neutralizing antibody could thus constitute an innovative therapeutic strategy for the treatment of CD146-positive tumors.
authors.affiliation: INSERM UMR-S 1076, Aix-Marseille University, UFR Pharmacy, Marseille, France.
authors.forename: J
authors.initials: J
authors.lastname: Stalin
authors.affiliation: INSERM UMR-S 1076, Aix-Marseille University, UFR Pharmacy, Marseille, France.
authors.forename: M
authors.initials: M
authors.lastname: Nollet
authors.affiliation: INSERM UMR-S 1076, Aix-Marseille University, UFR Pharmacy, Marseille, France.|CERIMED (European Center of Research in Medical Imaging), Aix-Marseille University, Marseille, France.
authors.forename: P
authors.initials: P
authors.lastname: Garigue
authors.affiliation: CERIMED (European Center of Research in Medical Imaging), Aix-Marseille University, Marseille, France.
authors.forename: S
authors.initials: S
authors.lastname: Fernandez
authors.affiliation: INSERM UMR-S 1076, Aix-Marseille University, UFR Pharmacy, Marseille, France.
authors.forename: L
authors.initials: L
authors.lastname: Vivancos
authors.affiliation: INSERM UMR-S 1076, Aix-Marseille University, UFR Pharmacy, Marseille, France.
authors.forename: A
authors.initials: A
authors.lastname: Essaadi
authors.affiliation: INSERM UMR-S 1076, Aix-Marseille University, UFR Pharmacy, Marseille, France.
authors.forename: A
authors.initials: A
authors.lastname: Muller
authors.affiliation: INSERM UMR-S 1076, Aix-Marseille University, UFR Pharmacy, Marseille, France.
authors.forename: R
authors.initials: R
authors.lastname: Bachelier
authors.affiliation: INSERM UMR-S 1076, Aix-Marseille University, UFR Pharmacy, Marseille, France.
authors.forename: A
authors.initials: A
authors.lastname: Foucault-Bertaud
authors.affiliation: Advanced Accelerator Applications SRL, Colleretto Giacosa (TO), Italy.
authors.forename: L
authors.initials: L
authors.lastname: Fugazza
authors.affiliation: INSERM UMR-S 1076, Aix-Marseille University, UFR Pharmacy, Marseille, France.
authors.forename: A S
authors.initials: AS
authors.lastname: Leroyer
authors.affiliation: INSERM UMR-S 1076, Aix-Marseille University, UFR Pharmacy, Marseille, France.
authors.forename: N
authors.initials: N
authors.lastname: Bardin
authors.affiliation: INSERM UMR-S 1076, Aix-Marseille University, UFR Pharmacy, Marseille, France.|CERIMED (European Center of Research in Medical Imaging), Aix-Marseille University, Marseille, France.
authors.forename: B
authors.initials: B
authors.lastname: Guillet
authors.affiliation: INSERM UMR-S 1076, Aix-Marseille University, UFR Pharmacy, Marseille, France.
authors.forename: F
authors.initials: F
authors.lastname: Dignat-George
authors.affiliation: INSERM UMR-S 1076, Aix-Marseille University, UFR Pharmacy, Marseille, France.
authors.forename: M
authors.initials: M
authors.lastname: Blot-Chabaud
mesh_terms: D000091082:Angiomotins; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D051929:CD146 Antigen / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism*; D011485:Protein Binding; D023041:Xenograft Model Antitumor Assays
chemical_list: C423985:AMOT protein, human; D000091082:Angiomotins; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015415:Biomarkers; D051929:CD146 Antigen; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins