title: Role of IL-8 induced angiogenesis in uveal melanoma.
abstract: 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.
authors.affiliation: Laboratory of Cancer Genetics and Translational Oncology, S. Croce General Hospital, Cuneo, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Lattanzio
authors.forename: Federica
authors.initials: F
authors.lastname: Tonissi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Torta
authors.forename: Luca
authors.initials: L
authors.lastname: Gianello
authors.forename: Elvio
authors.initials: E
authors.lastname: Russi
authors.forename: Gerard
authors.initials: G
authors.lastname: Milano
authors.forename: Marco
authors.initials: M
authors.lastname: Merlano
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lo Nigro
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D003131:Combined Modality Therapy; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D014604:Uveal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000098943:Uveal Melanoma
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D016209:Interleukin-8; D023063:Receptors, Interleukin-8B; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab
references.citation: J Skin Cancer. 2011;2011:573974
references.pmid: 21773036
references.citation: J Biol Chem. 2009 Mar 6;284(10):6038-42
references.pmid: 19112107
references.citation: Br J Ophthalmol. 2011 Jan;95(1):112-7
references.pmid: 20819828
references.citation: Br J Ophthalmol. 2002 Apr;86(4):448-52
references.pmid: 11914216
references.citation: Science. 1991 Sep 13;253(5025):1278-80
references.pmid: 1840701
references.citation: Curr Opin Oncol. 2012 Mar;24(2):162-9
references.pmid: 22234256
references.citation: Clin Cancer Res. 2008 Nov 1;14(21):6735-41
references.pmid: 18980965
references.citation: Dev Ophthalmol. 2012;49:117-136
references.pmid: 22042017
references.citation: Cancer Res. 1987 Feb 15;47(4):943-6
references.pmid: 3802101
references.citation: Science. 2005 Jan 7;307(5706):58-62
references.pmid: 15637262
references.citation: Invest Ophthalmol Vis Sci. 2005 May;46(5):1561-4
references.pmid: 15851551
references.citation: J Neurooncol. 2005 Sep;74(2):99-103
references.pmid: 16193379
references.citation: Cytokine. 2010 Apr;50(1):30-6
references.pmid: 20044268
references.citation: J Mol Med (Berl). 2000;78(10):554-61
references.pmid: 11199328
references.citation: Cancer Sci. 2008 Aug;99(8):1501-6
references.pmid: 18754859
references.citation: Invest Ophthalmol Vis Sci. 2012 Oct 01;53(11):6748-55
references.pmid: 22930720
references.citation: Br J Ophthalmol. 2000 Jul;84(7):750-6
references.pmid: 10873988
references.citation: Br J Cancer. 2009 May 19;100(10):1638-46
references.pmid: 19401689
references.citation: Cancer Res. 2010 Feb 1;70(3):1063-71
references.pmid: 20103651
references.citation: Invest New Drugs. 2013 Feb;31(1):59-65
references.pmid: 22714791