Advertisement

Investigational New Drugs

, Volume 31, Issue 5, pp 1107–1114 | Cite as

Role of IL-8 induced angiogenesis in uveal melanoma

  • Laura Lattanzio
  • Federica Tonissi
  • Ilaria Torta
  • Luca Gianello
  • Elvio Russi
  • Gerard Milano
  • Marco Merlano
  • Cristiana Lo NigroEmail author
PRECLINICAL STUDIES

Summary

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.

Keywords

Uveal melanoma IL-8 Angiogenesis VEGF 

Notes

Ethical standards

The authors declare that the experiments comply with the current laws of the country in which they were performed.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Sudaka A, Susini A, Lo Nigro C, Fischel JL, Toussan N, Formento P, Tonissi F, Lattanzio L, Russi E, Etienne-Grimaldi MC, Merlano M, Milano G (2013) Combination of bevacizumab and irradiation on uveal melanoma: an in vitro and in vivo study. Invest New Drugs 31:59–65. doi: https://doi.org/10.1007/s10637-012-9834-6 CrossRefGoogle Scholar
  2. 2.
    Papastefanou VO, Cohen VML (2011) Uveal melanoma. J Skin Cancer 2011:573974. doi: https://doi.org/10.1155/2011/573974 CrossRefGoogle Scholar
  3. 3.
    Leyvraz S, Keilholz U (2012) Ocular melanoma: what’s new? Curr Opin Oncol 24:162–169. doi: https://doi.org/10.1097/CCO.0b013e32834ff069 CrossRefGoogle Scholar
  4. 4.
    Sun Y, Tran BN, Worley LA, Delston RB, Harbour JW (2005) Functional Analysis of the p53 Pathway in Response to Ionizing Radiation in Uveal Melanoma. Invest Ophthalmol Vis Sci 46:1561–1564. doi: https://doi.org/10.1167/iovs.04-1362 CrossRefGoogle Scholar
  5. 5.
    Sheidow TG, Hooper PL, Crukley C, Young J, Heathcote JG (2000) Expression of vascular endothelial growth factor in uveal melanoma and its correlation with metastasis. Br J Ophtalmol 84:750–756. doi: https://doi.org/10.1136/bjo.84.7.750 CrossRefGoogle Scholar
  6. 6.
    Boyd SR, Tan DS, Bunce C, Gittos A, Neale MH, Hungerford JL, Charnock-Jones S, Cree IA (2002) Vascular endothelial growth factor is elevated in ocular fluids of eyes harbouring uveal melanoma: identification of a potential therapeutic window. Br J Ophtalmol 86:448–452CrossRefGoogle Scholar
  7. 7.
    Crosby MB, Yang H, Gao W, Zhang L, Grossniklaus HE (2011) Serum vascular endothelial growth factor (VEGF) levels correlate with number and location of micrometastases in a murine model of uveal melanoma. Br J Ophthalmol 95:112–117. doi: https://doi.org/10.1136/bjo.2010.182402 CrossRefGoogle Scholar
  8. 8.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62. doi: https://doi.org/10.1126/science.1104819 CrossRefGoogle Scholar
  9. 9.
    Hovinga KE, Stalpers LJ, van Bree C, Donker M, Verhoeff JJ, Rodermond HM, Bosch DA, van Furth WR (2005) Radiation-enhanced vascular endothelial growth factor (VEGF) secretion in glioblastoma multiforme cell lines–a clue to radioresistance? J Neurooncol 74:99–103. doi: https://doi.org/10.1007/s11060-004-4204-7 CrossRefGoogle Scholar
  10. 10.
    Waugh DJJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14:6735–6741. doi: https://doi.org/10.1158/1078-0432.CCR-07-4843 CrossRefGoogle Scholar
  11. 11.
    Holmes WE, Lee J, Kuang WJ, Rice GC, Wood WI (1991) Structure and functional expression of a human interleukin- 8 receptor. Science 253:1278–1280. doi: https://doi.org/10.1126/science.1840701 CrossRefGoogle Scholar
  12. 12.
    Singh S, Nannuru KC, Sadanandam A, Varney ML, Singh RK (2009) CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion. Br J Cancer 100:1638–1646. doi: https://doi.org/10.1038/sj.bjc.6605055 CrossRefGoogle Scholar
  13. 13.
    Martin D, Galisteo R, Gutkind S (2009) CXCL8/IL8 stimulates Vascular Endothelial Growth Factor (VEGF) expression and the autocrine activation of VEGFR2 in endothelial cells by activating NfkB through the CBM (Carma3/Bcl10/Malt) complex. J Biol Chem 284:6038–6042. doi: https://doi.org/10.1074/jbc.C800207200 CrossRefGoogle Scholar
  14. 14.
    Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, Kahnoski N, Futreal PA, Furge KA, Teh BT (2010) Interleukin-8 mediates resistance to anti-angiogenic agent Sunitinib in renal cell carcinoma. Cancer Res 70:1063–1071. doi: https://doi.org/10.1158/0008-5472 CrossRefGoogle Scholar
  15. 15.
    Nagarkatti-Gude N, Bronkhorst IH, van Duinen SG, Luyten GP, Jager MJ (2012) Cytokines and chemokines in the vitreous fluid of eyes with uveal melanoma. Invest Ophthalmol Vis Sci 53:6748–6755. doi: https://doi.org/10.1167/iovs.12-10123 CrossRefGoogle Scholar
  16. 16.
    Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of radiosensitivity. Cancer Res 47:943–946PubMedGoogle Scholar
  17. 17.
    Mantovani G, Maccio A, Mura L, Massa E, Mudu MC, Mulas C et al (2000) Serum levels of leptin and proinflammatory cytokines in patients with advancedstage cancer at different sites. J Mol Med 78:554–561CrossRefGoogle Scholar
  18. 18.
    Crohns M, Saarelainen S, Laine S, Poussa T, Alho H, Kellokumpu-Lehtinen P (2010) Cytokines in bronchoalveolar lavage fluid and serum of lung cancer patients during radiotherapy – Association of interleukin-8 and VEGF with survival. Cytokine 50:30–36. doi: https://doi.org/10.1016/j.cyto.2009.11.017 CrossRefGoogle Scholar
  19. 19.
    Ono M (2008) Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. Cancer Sci 99:1501–1506. doi: https://doi.org/10.1111/j.1349-7006.2008.00853 CrossRefGoogle Scholar
  20. 20.
    el Filali M, van der Velden PA, Luyten GP, Jager MJ (2012) Antiangiogenic therapy in uveal melanoma. Dev Ophthalmol 49:117–136. doi: https://doi.org/10.1159/000329591 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Laura Lattanzio
    • 1
  • Federica Tonissi
    • 1
  • Ilaria Torta
    • 1
  • Luca Gianello
    • 3
  • Elvio Russi
    • 3
  • Gerard Milano
    • 4
  • Marco Merlano
    • 2
  • Cristiana Lo Nigro
    • 1
    • 5
    Email author
  1. 1.Laboratory of Cancer Genetics and Translational OncologyS. Croce General HospitalCuneoItaly
  2. 2.Medical Oncology, Oncology DepartmentS. Croce General HospitalCuneoItaly
  3. 3.Radiotherapy DepartmentS. Croce General HospitalCuneoItaly
  4. 4.Oncopharmacology Unit EA 3836 UNSCentre Antoine LacassagneNiceFrance
  5. 5.Laboratory of Cancer Genetics and Translational Oncology, Oncology DepartmentS. Croce General HospitalCuneoItaly

Personalised recommendations