ZFIN ID: ZDB-PUB-110609-7
IGF binding protein-6 expression in vascular endothelial cells is induced by hypoxia and plays a negative role in tumor angiogenesis
Zhang, C., Lu, L., Li, Y., Wang, X., Zhou, J., Liu, Y., Fu, P., Gallicchio, M.A., Bach, L.A., and Duan, C.
Date: 2012
Source: International Journal of Cancer   30(9): 2003-2012 (Journal)
Registered Authors: Duan, Cunming, Zhou, Jianfeng
Keywords: none
MeSH Terms:
  • Animals
  • Cell Hypoxia
  • Cell Line, Tumor
  • Endothelial Cells/metabolism*
  • Female
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hypoxia-Inducible Factor 1/genetics
  • Hypoxia-Inducible Factor 1/metabolism
  • Insulin-Like Growth Factor Binding Protein 6/genetics
  • Insulin-Like Growth Factor Binding Protein 6/metabolism*
  • Insulin-Like Growth Factor I/genetics
  • Insulin-Like Growth Factor I/metabolism*
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic/genetics
  • Neovascularization, Pathologic/metabolism*
  • Neovascularization, Pathologic/pathology
  • Rats
  • Rhabdomyosarcoma/blood supply
  • Rhabdomyosarcoma/metabolism
  • Vascular Endothelial Growth Factor A/genetics
  • Vascular Endothelial Growth Factor A/metabolism*
  • Zebrafish
PubMed: 21618524 Full text @ Int. J. Cancer
Hypoxia stimulates tumor angiogenesis by inducing the expression of angiogenic molecules. The negative regulators of this process, however, are not well understood. Here we report that hypoxia induced the expression of insulin-like growth factor binding protein-6 (IGFBP-6), a tumor repressor, in human and rodent vascular endothelial cells (VECs) via a HIF-mediated mechanism. Addition of human IGFBP-6 to cultured human VECs inhibited angiogenesis in vitro. An IGFBP-6 mutant with at least 10,000-fold lower binding affinity for IGFs was an equally potent inhibitor of angiogenesis, suggesting that this action of IGFBP-6 is IGF-independent. The functional relationship between IGFBP-6 and VEGF, a major hypoxia-inducible angiogenic molecule, was examined. While VEGF alone increased angiogenesis in vitro, co-incubation with IGFBP-6 abolished VEGF-stimulated angiogenesis. The in vivo role of IGFBP-6 in angiogenesis was tested in flk1:GFP zebrafish embryos, which exhibit green fluorescence protein in developing vascular endothelium, permitting visualization of developing blood vessels. Injection of human IGFBP-6 mRNA reduced the number of embryonic inter-segmental blood vessels by ~40%. This anti-angiogenic activity is conserved in zebrafish because expression of zebrafish IGFBP-6b had similar effects. To determine the anti-angiogenic effect of IGFBP-6 in a tumor model, human Rh30 rhabdomyosarcoma cells stably transfected with IGFBP-6 were inoculated into athymic BALB/c nude mice. Vessel density was 52% lower in IGFBP-6-transfected xenografts than in vector control xenografts. These results suggest that the expression of IGFBP-6 in VECs is up-regulated by hypoxia and IGFBP-6 inhibits angiogenesis in vitro and in vivo.