Role of IL-8 induced angiogenesis in uveal melanoma

Invest New Drugs. 2013 Oct;31(5):1107-14. doi: 10.1007/s10637-013-0005-1. Epub 2013 Aug 4.


Introduction Uveal melanoma (UM) is a highly vascularised tumour generally treated with radiotherapy (RT). A recent preclinical study from our group [1] demonstrated that RT-associated anti-angiogenic therapy has more than additive effects on cell growth, by modulating vascular endothelial growth factor (VEGF) levels. The pro-angiogenic interleukin-8 (IL-8) is highly expressed in both tumour and endothelial cells and is associated with resistance to VEGF-targeted therapies in various tumour types. The aim of this study is to investigate IL-8 release in response to the anti-angiogenic drug bevacizumab (AV) and RT given alone and in combination. Material and methods The human ocular melanoma cells (OCM-1) and human umbilical vein endothelial cells (HUVEC) were grown in transwell plates. AV was administered at a 2,500 μg/ml dose and cells were irradiated with a 6 Gy dose. IL-8 concentrations were determined by ELISA assay. Protein expression was detected by western blot. Results AV alone or in combination with RT reduces VEGF levels in both cell lines when co-cultured; unexpectedly, RT alone did not increase VEGF levels. In transwell plate AV alone lowered IL-8 secretion in both cell lines. This inhibitory effect was reduced when co-cultured cells are treated with AV + RT, suggesting that RT-induced VEGF may reactivate IL-8 secretion, enhancing an alternative pathway to sustain tumour angiogenesis. Conclusions These data indicate that the UM microenvironment, beside VEGF, can activate IL-8 signalling as an alternative pro-angiogenic pathway.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Bevacizumab
  • Cell Line, Tumor
  • Cells, Cultured
  • Coculture Techniques
  • Combined Modality Therapy
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Interleukin-8 / metabolism*
  • Melanoma / drug therapy
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Melanoma / radiotherapy
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Pathologic / radiotherapy
  • Receptors, Interleukin-8B / metabolism
  • Uveal Neoplasms / drug therapy
  • Uveal Neoplasms / metabolism*
  • Uveal Neoplasms / pathology
  • Uveal Neoplasms / radiotherapy
  • Vascular Endothelial Growth Factor A / metabolism


  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal, Humanized
  • Interleukin-8
  • Receptors, Interleukin-8B
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Bevacizumab

Supplementary concepts

  • Uveal melanoma