title: N-myc oncogene overexpression down-regulates IL-6; evidence that IL-6 inhibits angiogenesis and suppresses neuroblastoma tumor growth.
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.
authors.affiliation: Laboratory of Biological Chemistry, Medical School, University of Ioannina, Ioannina, Greece.
authors.forename: Elissavet
authors.initials: E
authors.lastname: Hatzi
authors.forename: Carol
authors.initials: C
authors.lastname: Murphy
authors.forename: Andreas
authors.initials: A
authors.lastname: Zoephel
authors.forename: Heidi
authors.initials: H
authors.lastname: Rasmussen
authors.forename: Lucia
authors.initials: L
authors.lastname: Morbidelli
authors.forename: Horst
authors.initials: H
authors.lastname: Ahorn
authors.forename: Keita
authors.initials: K
authors.lastname: Kunisada
authors.forename: Ulrike
authors.initials: U
authors.lastname: Tontsch
authors.forename: Michael
authors.initials: M
authors.lastname: Klenk
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamauchi-Takihara
authors.forename: Marina
authors.initials: M
authors.lastname: Ziche
authors.forename: Einar K
authors.initials: EK
authors.lastname: Rofstad
authors.forename: Lothar
authors.initials: L
authors.lastname: Schweigerer
authors.forename: Theodore
authors.initials: T
authors.lastname: Fotsis
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016543:Central Nervous System Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D003315:Cornea / Q000098:blood supply / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000628:therapy; D009447:Neuroblastoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D016274:Oncogene Protein p55(v-myc) / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011817:Rabbits; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016274:Oncogene Protein p55(v-myc); D012334:RNA, Neoplasm; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators