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.
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Acknowledgements
We would like to thank the confocal laser microscope facility of the University of Ioannina for the use of the Leica TCS-SP confocal microscope. The skillful technical support of Lambrini Kyrkou is gratefully acknowledged. This work was supported by Boehringer Ingelheim Austria GmbH, Vienna, Austria, Deutsche Forschungsgemeinschaft and a grant from the Joint Research and Technology Program between Greece (General Secretariat of Research and Technology) and Germany (T Fotsis and L Schweigerer). Mice xenograft experients were financed by the Norwegian Cancer Society (EK Rofstad). E Hatzi was supported by a postdoctoral grant from the State Award Foundation of Greece.
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Hatzi, E., Murphy, C., Zoephel, A. et al. N-myc oncogene overexpression down-regulates IL-6; evidence that IL-6 inhibits angiogenesis and suppresses neuroblastoma tumor growth. Oncogene 21, 3552–3561 (2002). https://doi.org/10.1038/sj.onc.1205440
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DOI: https://doi.org/10.1038/sj.onc.1205440
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