Abstract
Angiogenesis is an indispensable prerequisite for the progression and metastasis of solid malignancies. Tumor angiogenesis appears to be governed by alterations of tumor suppressor or oncogenes operant in a broad range of tumors. We have addressed this issue in neuroblastoma, a malignancy characterized by the near-exclusive amplification and overexpression of the N-Myc oncogene. Here, we report that N-Myc overexpression results in down-regulation of interleukin-6 (IL-6) and that IL-6 is an inhibitor of endothelial cell proliferation and VEGF-induced rabbit corneal angiogenesis. STAT3 is instrumental for IL-6 activity as infection with adenoviruses expressing a phosphorylation deficient STAT3 mutant renders endothelial cells insensitive to the antiproliferative action of IL-6. Finally, though IL-6 does not influence neuroblastoma cell growth, IL-6-expressing xenograft tumors in mice exhibit reduced neovascularization and suppressed growth. Our data shed new light on the mechanisms by which N-myc oncogene amplification enhances the malignant phenotype in neuroblastomas.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / metabolism
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Angiogenesis Inhibitors / pharmacology
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Angiogenesis Inhibitors / physiology*
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Animals
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology
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Cattle
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Cell Division / drug effects
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Cells, Cultured
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Central Nervous System Neoplasms / blood supply
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Central Nervous System Neoplasms / metabolism
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Central Nervous System Neoplasms / pathology
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Central Nervous System Neoplasms / therapy
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Cornea / blood supply
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Cornea / drug effects
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DNA-Binding Proteins / metabolism
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Down-Regulation
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Female
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Gene Expression Regulation, Neoplastic
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Interleukin-6 / metabolism*
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Interleukin-6 / pharmacology
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Interleukin-6 / physiology*
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neovascularization, Pathologic* / therapy
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Neuroblastoma / blood supply*
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Neuroblastoma / metabolism
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Neuroblastoma / pathology
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Neuroblastoma / therapy
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Oncogene Protein p55(v-myc) / genetics*
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Oncogene Protein p55(v-myc) / metabolism
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RNA, Neoplasm / biosynthesis
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Rabbits
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STAT3 Transcription Factor
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Trans-Activators / metabolism
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Transfection
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Tumor Cells, Cultured
Substances
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Angiogenesis Inhibitors
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Antineoplastic Agents
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DNA-Binding Proteins
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Interleukin-6
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Oncogene Protein p55(v-myc)
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RNA, Neoplasm
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Trans-Activators