Abstract
Inhibiting the growth of tumor vasculature represents one of the relevant strategies against tumor progression. Between all the different pro-angiogenic molecular targets, plasma membrane glycosphingolipids have been under-investigated. In this present study, we explore the anti-angiogenic therapeutic advantage of a tumor immunotherapy targeting the globotriaosylceramide Gb3. In this purpose, a monoclonal antibody against Gb3, named 3E2 was developed and characterized. We first demonstrate that Gb3 is over-expressed in proliferative endothelial cells relative to quiescent cells. Then, we demonstrate that 3E2 inhibits endothelial cell proliferation in vitro by slowing endothelial cell proliferation and by increasing mitosis duration. Antibody 3E2 is further effective in inhibiting ex vivo angiogenesis in aorta ring assays. Moreover, 3E2 treatment inhibits NXS2 neuroblastoma development and liver metastases spreading in A/J mice. Immunohistology examination of the NXS2 metastases shows that only endothelial cells, but not cancer cells express Gb3. Finally, 3E2 treatment diminishes tumor vessels density, proving a specific therapeutic action of our monoclonal antibody to tumor vasculature. Our study demonstrates that Gb3 is a viable alternative target for immunotherapy and angiogenesis inhibition.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / administration & dosage
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal / immunology*
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Antibodies, Monoclonal / pharmacology*
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Antigens, Tumor-Associated, Carbohydrate / immunology*
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Antigens, Tumor-Associated, Carbohydrate / metabolism
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacology*
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Cell Line
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Cell Line, Tumor
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Cell Proliferation
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Cell Transformation, Neoplastic / drug effects*
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Cell Transformation, Neoplastic / immunology*
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Disease Models, Animal
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Human Umbilical Vein Endothelial Cells / immunology
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Male
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Mice
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Neoplasm Metastasis
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / immunology*
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Neovascularization, Physiologic / drug effects
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Neuroblastoma / drug therapy
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Neuroblastoma / immunology
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Neuroblastoma / pathology
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Tumor Burden / drug effects
Substances
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Angiogenesis Inhibitors
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Antibodies, Monoclonal
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Antigens, Tumor-Associated, Carbohydrate
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Antineoplastic Agents
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Gb3 antigen
Grants and funding
The present work was supported by La Ligue Nationale Contre le Cancer and the Fondation de l'Université de Nantes (Aair Lichens). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.