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 ampli®cation 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 de®cient STAT3 mutant renders endothelial cells insensitive to the antiproliferative action of IL-6. Finally, though IL-6 does not in¯uence 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 ampli®cation enhances the malignant phenotype in neuroblastomas.

A Critical Role for Mast Cells and Mast Cell-Derived IL-6 in TLR2-Mediated Inhibition of Tumor Growth

“…Studies in mast cell-deficient Kit W /Kit Wv mice, using the B16.BL6 melanoma model, demonstrated that delayed tumor growth kinetics in mast cell-deficient mice is attributable to a delayed and decreased angiogenic response (13). Mast cell IL-6-dependent angiogenesis suppression is consistent with previous findings that IL-6-mediated melanoma growth inhibition is independent of B and T cell responses (41) and that the antitumor action of IL-6 is due in part to angiogenesis inhibition (53). Further, IL-6-transfected B16.F10 tumors exhibit a significant decrease in angiogenesis via an in vivo intradermal angiogenesis assay (40).…”

Mechanisms for Lysophosphatidic Acid-induced Cytokine Production in Ovarian Cancer Cells

“…Compared with IL-8, a role for IL-6 in angiogenesis is controversial. Although IL-6 may inhibit endothelial cell proliferation (56), it increases the motility and proper alignment of endothelial cells (57). In the ovary, strong evidence suggests that IL-6 is produced and participates in vascular remodeling during the development of ovarian follicles (58).…”

Transcription factors: their potential as targets for an individualized therapeutic approach to cancer

“…28,29 N-Myc overexpression has been identified in several types of cancer (retinoblastoma, 30 small-cell lung cancer 31 and medulloblastoma 29 ) and has been shown to affect angiogenesis, in part, through the modulation of IL6. 32 Hatzi et al 32 have recently demonstrated that N-Myc amplification enhances the malignant phenotype in neuroblastoma.…”