Abstract
Notch signaling is required for vascular development and tumor angiogenesis. Although inhibition of the Notch ligand Delta-like 4 can restrict tumor growth and disrupt neovasculature, the effect of inhibiting Notch receptor function on angiogenesis has yet to be defined. In this study, we generated a soluble form of the Notch1 receptor (Notch1 decoy) and assessed its effect on angiogenesis in vitro and in vivo. Notch1 decoy expression reduced signaling stimulated by the binding of three distinct Notch ligands to Notch1 and inhibited morphogenesis of endothelial cells overexpressing Notch4. Thus, Notch1 decoy functioned as an antagonist of ligand-dependent Notch signaling. In mice, Notch1 decoy also inhibited vascular endothelial growth factor-induced angiogenesis in skin, establishing a role for Notch receptor function in this process. We tested the effects of Notch1 decoy on tumor angiogenesis using two models: mouse mammary Mm5MT cells overexpressing fibroblast growth factor 4 (Mm5MT-FGF4) and NGP human neuroblastoma cells. Exogenously expressed FGF4 induced Notch ligand expression in Mm5MT cells and xenografts. Notch1 decoy expression did not affect tumorigenicity of Mm5MT-FGF4 cells in vitro but restricted Mm5MT-FGF4 xenograft growth in mice while markedly impairing neoangiogenesis. Similarly, Notch1 decoy expression did not affect NGP cells in vitro but disrupted vessels and decreased tumor viability in vivo. These results strongly suggest that Notch receptor signaling is required for tumor neoangiogenesis and provides a new target for tumor therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Calcium-Binding Proteins / metabolism
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism
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Fibroblast Growth Factor 4 / metabolism
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Humans
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Immunoenzyme Techniques
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Intercellular Signaling Peptides and Proteins / metabolism
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Mammary Neoplasms, Animal / blood supply
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Mammary Neoplasms, Animal / metabolism
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Mammary Neoplasms, Animal / pathology
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Mammary Neoplasms, Animal / prevention & control*
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Nude
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Neovascularization, Pathologic / prevention & control*
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Neuroblastoma / blood supply*
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Neuroblastoma / pathology
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / physiology*
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Receptor, Notch1 / antagonists & inhibitors
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Receptor, Notch1 / physiology*
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Receptor, Notch4
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Receptors, Notch / antagonists & inhibitors
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Receptors, Notch / physiology*
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Serrate-Jagged Proteins
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Signal Transduction*
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Skin / metabolism
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Skin / pathology
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Transplantation, Heterologous
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Tumor Cells, Cultured
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Umbilical Veins / cytology
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Umbilical Veins / metabolism
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Vascular Endothelial Growth Factor A / antagonists & inhibitors
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Calcium-Binding Proteins
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Dlk1 protein, mouse
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Fgf4 protein, mouse
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Fibroblast Growth Factor 4
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Intercellular Signaling Peptides and Proteins
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Membrane Proteins
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NOTCH4 protein, human
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Proto-Oncogene Proteins
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Receptor, Notch1
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Receptor, Notch4
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Receptors, Notch
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Serrate-Jagged Proteins
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VEGFA protein, human
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Vascular Endothelial Growth Factor A