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N-myc oncogene overexpression down-regulates IL-6; evidence that IL-6 inhibits angiogenesis and suppresses neuroblastoma tumor growth

Oncogene volume 21, pages 3552–3561 (2002)Cite this article

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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References

  • Ambrosino C, Ruocco MR, Chen X, Mallardo M, Baudi F, Trematerra S, Quinto I, Venuta S, Scala G . 1997 J. Biol. Chem. 272: 14883–14892

  • Bannasch D, Weis I, Schwab M . 1999 Oncogene 18: 6810–6817

  • Bartoli M, Gu X, Tsai NT, Venema RC, Brooks SE, Marrero MB, Caldwell RB . 2000 J. Biol. Chem. 275: 33189–33192

  • Bellido T, O'Brien CA, Roberson PK, Manolagas SC . 1998 J. Biol. Chem. 273: 21137–21144

  • Blackwood EM, Eisenman RN . 1991 Science 251: 1211–1217

  • Bouck N, Stellmach V, Hsu SC . 1996 Adv. Cancer Res. 69: 135–174

  • Breit S, Ashman K, Wilting J, Rossler J, Hatzi E, Fotsis T, Schweigerer L . 2000 Cancer Res. 60: 4596–4601

  • Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM . 1984 Science 224: 1121–1124

  • Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell Jr JE . 1998 Mol. Cell. Biol. 18: 2553–2558

  • Dameron KM, Volpert OV, Tainsky MA, Bouck N . 1994 Science 265: 1582–1584

  • Danielsen T, Rofstad EK . 1998 Int. J. Cancer 76: 836–841

  • Facchini LM, Penn LZ . 1998 FASEB J. 12: 633–651

  • Fee D, Grzybicki D, Dobbs M, Ihyer S, Clotfelter J, Macvilay S, Hart MN, Sandor M, Fabry Z . 2000 Cytokine 12: 655–665

  • Fotsis T, Breit S, Lutz W, Rossler J, Hatzi E, Schwab M, Schweigerer L . 1999 Eur. J. Biochem. 263: 757–764

  • Fotsis T, Pepper MS, Aktas E, Breit S, Rasku S, Adlercreutz H, Wahala K, Montesano R, Schweigerer L . 1997 Cancer Res. 57: 2916–2921

  • Grady-Leopardi E, Schwab M, Ablin A, Rosenau W . 1986 Cancer Res. 46: 3196–3199

  • Grandori C, Eisenman RN . 1997 Trends Biochem. Sci. 22: 177–181

  • Guo QM, Malek RL, Kim S, Chiao C, He M, Ruffy M, Sanka K, Lee NH, Dang CV, Liu ET . 2000 Cancer Res. 60: 5922–5928

  • Hanahan D, Folkman J . 1996 Cell 86: 353–364

  • Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L . 1998 Biochem. J. 334: 297–314

  • Hiller S, Breit S, Wang ZQ, Wagner EF, Schwab M . 1991 Oncogene 6: 969–977

  • Korpelainen EI, Karkkainen M, Gunji Y, Vikkula M, Alitalo K . 1999 Oncogene 18: 1–8

  • Kortylewski M, Heinrich PC, Mackiewicz A, Schniertshauer U, Klingmuller U, Nakajima K, Hirano T, Horn F, Behrmann I . 1999 Oncogene 18: 3742–3753

  • Kunisada K, Tone E, Fujio Y, Matsui H, Yamauchi-Takihara K, Kishimoto T . 1998 Circulation 98: 346–352

  • Lee LA, Dolde C, Barrett J, Wu CS, Dang CV . 1996 J. Clin. Invest. 97: 1687–1695

  • Liotta LA, Steeg PS, Stetler-Stevenson WG . 1991 Cell 64: 327–336

  • Mac SM, D'Cunha CA, Farnham PJ . 2000 Mol. Carcinog. 29: 76–86

  • Matsui H, Ihara Y, Fujio Y, Kunisada K, Akira S, Kishimoto T, Yamauchi-Takihara K . 1999 Cardiovasc. Res. 42: 104–112

  • Megeney LA, Perry RL, LeCouter JE, Rudnicki MA . 1996 Dev. Genet. 19: 139–145

  • Meitar D, Crawford SE, Radmaker AW, Cohn SL . 1996 J. Clin. Oncol. 14: 405–414

  • Motro B, Itin A, Sachs L, Keshet E . 1990 Proc. Natl. Acad. Sci. USA 87: 3092–3096

  • Ohe Y, Podack ER, Olsen KJ, Miyahara Y, Miura K, Saito H, Koishihara Y, Ohsugi Y, Ohira T, Nishio K, Saijon N . 1993 Br. J. Cancer 67: 939–944

  • Prendergast GC, Ziff EB . 1991 Science 251: 186–189

  • Ray A, LaForge KS, Sehgal PB . 1990 Mol. Cell. Biol. 10: 5736–5746

  • Rofstad EK, Halsor EF . 2000 Cancer Res. 60: 4932–4938

  • Schweigerer L, Breit S, Wenzel A, Tsunamoto K, Ludwig R, Schwab M . 1990 Cancer Res. 50: 4411–4416

  • Shrivastava A, Saleque S, Kalpana GV, Artandi S, Goff SP, Calame K . 1993 Science 262: 1889–1892

  • Van Meir EG, Polverini PJ, Chazin VR, Su Huang H-J, De Tribolet N, Cavenee WK . 1994 Nature Genet. 8: 171–176

  • Zhu M, John S, Berg M, Leonard WJ . 1999 Cell 96: 121–130

  • Ziche M, Morbidelli L, Choudhuri R, Zhang HT, Donnini S, Granger HJ, Bicknell R . 1997 J. Clin. Invest. 99: 2625–2634

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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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Author notes

  1. Lothar Schweigerer and Theodore Fotsis: L Schweigerer and T Fotsis contributed equally to this study

Authors and Affiliations

  1. Laboratory of Biological Chemistry, Medical School, University of Ioannina, Ioannina, Greece

    Elissavet Hatzi, Carol Murphy & Theodore Fotsis

  2. Ioannina Biomedical Research Institute, Ioannina, Greece

    Carol Murphy

  3. Boehringer Ingelheim Austria GmbH, Vienna, Austria

    Andreas Zoephel, Horst Ahorn & Ulrike Tontsch

  4. Department of Biophysics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway

    Heidi Rasmussen & Einar K Rofstad

  5. Institute of Pharmacological Sciences, University of Siena, Siena, Italy

    Lucia Morbidelli & Marina Ziche

  6. Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita, Japan

    Keita Kunisada & Keiko Yamauchi-Takihara

  7. Abt. Hämatologie, Onkologie und Endokrinologie, Universitäts-Kinderklinik Essen, Essen, Germany

    Michael Klenk & Lothar Schweigerer

Authors
  1. Elissavet Hatzi
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Correspondence to Theodore Fotsis.

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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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