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

• Published in: Oncogene Vol. 21; no. 22; pp. 3552 - 3561
• Main Authors: HATZI, Elissavet, MURPHY, Carol, ZICHE, Marina, ROFSTAD, Einar K, SCHWEIGERER, Lothar, FOTSIS, Theodore, ZOEPHEL, Andreas, RASMUSSEN, Heidi, MORBIDELLI, Lucia, AHORN, Horst, KUNISADA, Keita, TONTSCH, Ulrike, KLENK, Michael, YAMAUCHI-TAKIHARA, Keiko
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 16.05.2002; Nature Publishing Group
• Subjects: Angiogenesis; Angiogenesis Inhibitors - metabolism; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - physiology; Animals; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cancer; Cattle; Cell Division - drug effects; Cell growth; Cell physiology; Cell proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cells, Cultured; Central Nervous System Neoplasms - blood supply; Central Nervous System Neoplasms - metabolism; Central Nervous System Neoplasms - pathology; Central Nervous System Neoplasms - therapy; Cornea; Cornea - blood supply; Cornea - drug effects; DNA-Binding Proteins - metabolism; Down-Regulation; Endothelial cells; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; Interleukin 6; Interleukin-6 - metabolism; Interleukin-6 - pharmacology; Interleukin-6 - physiology; Malignancy; Medical research; Metastases; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular and cellular biology; Myc protein; Neovascularization, Pathologic - therapy; Neuroblastoma; Neuroblastoma - blood supply; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neuroblastoma - therapy; Oncogene Protein p55(v-myc) - genetics; Oncogene Protein p55(v-myc) - metabolism; Oncogenes; Operant conditioning; Phenotypes; Phosphorylation; Rabbits; RNA, Neoplasm - biosynthesis; Stat3 protein; STAT3 Transcription Factor; Trans-Activators - metabolism; Transfection; Tumor Cells, Cultured; Tumor suppressor genes; Tumors; Vascular endothelial growth factor; Vascularization; Xenografts; Greece; Austria; Human; Nervous system diseases; Endothelial cell; Rodentia; Malignant tumor; Neuroblastoma; Sympathetic nervous system; Heterograft; Carcinogenesis; Interleukin 6; Angiogenesis; Vertebrata; Mammalia; Cell line; Mouse; C-Onc gene; Transcription factor STAT3; Graft; Transcription factor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1205440

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.