title: Disturbed melanin synthesis and chronic oxidative stress in dysplastic naevi.
abstract: Dysplastic naevi (DN) are a known risk factor for malignant melanoma. Their occurrence is closely connected with the degree of skin pigmentation. People with a light complexion are more likely to develop DN than dark-skinned individuals. We examined the proposition that DN exhibit altered melanin formation, which may be involved in their malignant transformation. X-ray microanalysis was used to study the composition of melanosomes from DN and to compare the results with those obtained from melanomas, banal (dermal) naevi and normal cutaneous melanocytes. We analysed sulphur (an indicator of phaeomelanin) and two metals, iron and calcium, involved in oxidative stress. FACS analysis of dihydrorhodamine-123-labelled cells was employed to quantify differences in the production of radical oxygen species in DN cells and normal skin melanocytes. A significantly higher sulphur content was found in melanosomes from DN cells and melanoma cells when compared with normal melanocytes and naevus cells from banal naevi. In addition, melanosomes of DN cells and melanoma cells contained higher amounts of iron and calcium. In the case of calcium, this was associated with a significantly elevated cytoplasmic concentration. FACS analysis showed that DN cells exhibited higher concentrations of radical oxygen species than normal skin melanocytes from the same individuals. We propose that increased phaeomelanogenesis in DN cells is connected with oxidative imbalance, which is reflected by increased intracellular concentrations of reactive oxygen species and raised calcium and iron concentrations. We show that the metabolic alterations in DN cells resemble those found in melanoma cells. Our findings provide support for the idea that DN cells are true precursor lesions of melanoma.
authors.affiliation: Department of Dermatology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC Leiden, The Netherlands. s.pavel@lumc.nl
authors.forename: Stan
authors.initials: S
authors.lastname: Pavel
authors.forename: Frans
authors.initials: F
authors.lastname: van Nieuwpoort
authors.forename: Hans
authors.initials: H
authors.lastname: van der Meulen
authors.forename: Coby
authors.initials: C
authors.lastname: Out
authors.forename: Karel
authors.initials: K
authors.lastname: Pizinger
authors.forename: Petra
authors.initials: P
authors.lastname: Cetkovská
authors.forename: Nico P M
authors.initials: NP
authors.lastname: Smit
authors.forename: Henk K
authors.initials: HK
authors.lastname: Koerten
mesh_terms: D002118:Calcium / Q000032:analysis; D004416:Dysplastic Nevus Syndrome / Q000378:metabolism*; D004577:Electron Probe Microanalysis; D005434:Flow Cytometry; D006801:Humans; D007501:Iron / Q000032:analysis; D008543:Melanins / Q000032:analysis / Q000096:biosynthesis*; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009506:Nevus / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D012878:Skin Neoplasms / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: D008543:Melanins; D017382:Reactive Oxygen Species; D007501:Iron; D002118:Calcium