title: Tumor necrosis factor alpha increases and alpha-melanocyte-stimulating hormone reduces uveal melanoma invasion through fibronectin.
abstract: Iris melanomas are less likely to metastasize than posterior compartment melanomas. The anterior chamber of the eye is an immunosuppressed microenvironment where a wide range of immunosuppressive factors in aqueous humor contribute to the immune privilege. One such factor is alpha-melanocyte-stimulating hormone, a potent anti-inflammatory neuropeptide that exhibits efficacy in many studies of acute and chronic inflammation. The aim of this study was to investigate whether the different metastatic behavior of iris melanomas versus posterior compartment melanomas might be explained by the differing immunosuppressive/anti-inflammatory environments of these tumors in vivo. To investigate this hypothesis, we studied the effect of human aqueous and vitreous fluids, of the proinflammatory cytokine tumor necrosis factor alpha, and of the anti-inflammatory peptides alpha-melanocyte-stimulating hormone and melanocyte-stimulating hormone 11-13 (KP-D-V) on the invasion of three human uveal melanoma cell lines through human fibronectin. Fresh aqueous humor samples significantly decreased the invasion in two out of three uveal melanoma cell lines. In contrast, vitreous humor did not reduce invasion. Tumor necrosis factor alpha significantly increased the invasiveness of uveal melanoma cell lines by approximately 50%-80% over 20 h. Full-length alpha-melanocyte-stimulating hormone, at concentrations present in the aqueous humor (10-9 M), as well as melanocyte-stimulating hormone 11-13 (KP-D-V) reduced the invasion of cells through human fibronectin by 45%-50% and also protected uveal melanoma cells from the pro-invasive actions of tumor necrosis factor alpha. These data are consistent with inflammation playing a major role in affecting the metastatic ability of uveal melanomas. Thus, ocular microenvironments that differ in their immunosuppressive/anti-inflammatory properties may influence the invasiveness of developing tumors.
authors.affiliation: Section of Human Metabolism, Division of Clinical Sciences (North), Northern General Hospital, Sheffield S5 7AU, UK.
authors.forename: Irene
authors.initials: I
authors.lastname: Cantón
authors.forename: Paula C
authors.initials: PC
authors.lastname: Eves
authors.forename: Marika
authors.initials: M
authors.lastname: Szabo
authors.forename: Fernando
authors.initials: F
authors.lastname: Vidal-Vanaclocha
authors.forename: Karen
authors.initials: K
authors.lastname: Sisley
authors.forename: Ian G
authors.initials: IG
authors.lastname: Rennie
authors.forename: John W
authors.initials: JW
authors.lastname: Haycock
authors.forename: Sheila
authors.initials: S
authors.lastname: MacNeil
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001082:Aqueous Humor; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D015811:Iris Neoplasms; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D008545:Melanoma; D009361:Neoplasm Invasiveness; D010446:Peptide Fragments / Q000494:pharmacology; D018043:Receptors, Corticotropin / Q000378:metabolism; D044101:Receptors, Melanocortin; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014604:Uveal Neoplasms; D014822:Vitreous Body; D000521:alpha-MSH / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D005353:Fibronectins; D010446:Peptide Fragments; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D014409:Tumor Necrosis Factor-alpha; D000521:alpha-MSH; C043156:MSH (11-13); D009074:Melanocyte-Stimulating Hormones