Molecular pathogenesis of malignant melanoma: a different perspective from the studies of melanocytic nevus and acral melanoma

The Clark model for melanoma progression emphasizes a series of histopathological changes beginning from benign melanocytic nevus to melanoma via dysplastic nevus. Several models of the genetic basis of melanoma development and progression are based on this Clark’s multi-step model, and predict that the acquisition of a BRAF mutation can be a founder event in melanocytic neoplasia. However, our recent investigations have challenged this view, showing the polyclonality of BRAF mutations in melanocytic nevi. Furthermore, it is suggested that many melanomas, including acral and mucosal melanomas, arise de novo, not from melanocytic nevus. While mutations of the BRAF gene are frequent in melanomas on non-chronic sun damaged skin which are prevalent in Caucasians, acral and mucosal melanomas harbor mutations of the KIT gene as well as the amplifications of cyclin D1 or cyclin-dependent kinase 4 gene. Amplifications of the cyclin D1 gene are detected in normal-looking ‘field melanocytes’, which represent a latent progression phase of acral melanoma that precedes the stage of atypical melanocyte proliferation in the epidermis. Based on these observations, we propose an alternative genetic progression model for melanoma.     

Selection for skin color among the Japanese

A reflectance spectrophotometer was used to record the skin color on the inner side of the upper arm on a series of 421 Japanese students of both sexes aged 15 through 19. All geographic regions in the country, and the upper, middle and lower socioeconomic classes were represented. It was found that, as among most peoples previously studied, males are darker than females. Boys from northern Japan are, on average, a bit lighter than are those from the southwest, but there are no geographically based differences among the girls. In both sexes and all areas, the mean reflectance values of the upper class group are higher than in the middle and lower class groups, but the difference is most pronounced among the males. It is therefore concluded that social selection for light skin color has had some genetic effect.     

Acral lentiginous melanoma: Basic facts,biological characteristics and research perspectives of an understudied disease

Acral lentiginous melanoma is a histological subtype of cutaneous melanoma that occurs in the glabrous skin of the palms, soles and the nail unit. Although in some countries, particularly in Latin America, Africa and Asia, it represents the most frequently diagnosed subtype of the disease, it only represents a small proportion of melanoma cases in European‐descent populations, which is partially why it has not been studied to the same extent as other forms of melanoma. As a result, its unique genomic drivers remain comparatively poorly explored, as well as its causes, with current evidence supporting a UV‐independent path to tumorigenesis. In this review, we discuss current knowledge of the aetiology and diagnostic criteria of acral lentiginous melanoma, as well as its epidemiological and histopathological characteristics. We also describe what is known about the genomic landscape of this disease and review the available biological models to explore potential therapeutic targets.     

Identification of the hereditary variants of skin melanoma

The identification of hereditary variants of cutaneous melanoma and analysis of the role of hereditary factors and syndromes predisposing to cutaneous melanoma were carried out. The involvement of individual nevus phenotypes in the development of this disease was determined. Based on a survey of recent molecular biological data and our studies, the etiological and genetic heterogeneity of cutaneous melanoma is reported. In relatives of patients with cutaneous melanoma and persons with multiple pigmented nevi, the malignant tumors proved to be differentiated in the direction of the neural crist tissues and/or derivatives of cutaneous mesenchyma. Based on the evidence obtained, the approaches have been developed to formation of risk groups for the purpose of early diagnostics of cutaneous melanoma.     

Technical Note: Comparing von Luschan skin color tiles and modern spectrophotometry for measuring human skin pigmentation

Prior to the introduction of reflectance spectrophotometry into anthropological field research during the 1950s, human skin color was most commonly classified by visual skin color matching using the von Luschan tiles, a set of 36 standardized, opaque glass tiles arranged in a chromatic scale. Our goal was to establish a conversion formula between the tile‐based color matching method and modern reflectance spectrophotometry to make historical and contemporary data comparable. Skin pigmentation measurements were taken on the forehead, inner upper arms, and backs of the hands using both the tiles and a spectrophotometer on 246 participants showing a broad range of skin pigmentation. From these data, a second‐order polynomial conversion formula was derived by jackknife analysis to estimate melanin index (M‐index) based on tile values. This conversion formula provides a means for comparing modern data to von Luschan tile measurements recorded in historical reports. This is particularly important for populations now extinct, extirpated, or admixed for which tile‐based measures of skin pigmentation are the only data available. Am J Phys Anthropol 151:325–330, 2013. © 2013 Wiley Periodicals, Inc.     

Low educational attainment is still associated with late melanoma diagnosis: A cross-sectional study from a European setting with universal healthcare

BackgroundAn early diagnosis of cutaneous melanoma remains determinant for improved survival. Low educational attainment has been associated with a late-stage diagnosis in settings where access to healthcare is restricted. Little evidence is available from regions with universal healthcare. We aimed at analysing whether educational attainment was associated with Breslow thickness at diagnosis in a peripheral European region with universal healthcare (in the Canary Islands, Spain).MethodsWe conducted a cross-sectional study with prospectively collected data (2010–2017). Patients were recruited at diagnosis, and information about Breslow thickness, age at diagnosis, gender, highest educational attainment and site of melanoma were registered. Univariate and multivariate linear regression analyses were performed.ResultsLow educational attainment was associated with thicker tumours at diagnosis. The association remained true after adjustment for age, gender and site of melanoma. In the multivariate analysis, tumours diagnosed in patients with low educational attainment were on average 1.08 mm thicker (95% confidence interval: 0.36–1.81; p = 0.003) than those diagnosed in patients with high educational attainment.ConclusionPublic health strategies targeting this vulnerable group are currently needed in the Canary Islands (Spain).     

How fish color their skin: A paradigm for development and evolution of adult patterns

Pigment cells in zebrafish ? melanophores, iridophores, and xanthophores ? originate from neural crest‐derived stem cells associated with the dorsal root ganglia of the peripheral nervous system. Clonal analysis indicates that these progenitors remain multipotent and plastic beyond embryogenesis well into metamorphosis, when the adult color pattern develops. Pigment cells share a lineage with neuronal cells of the peripheral nervous system; progenitors propagate along the spinal nerves. The proliferation of pigment cells is regulated by competitive interactions among cells of the same type. An even spacing involves collective migration and contact inhibition of locomotion of the three cell types distributed in superimposed monolayers in the skin. This mode of coloring the skin is probably common to fish, whereas different patterns emerge by species specific cell interactions among the different pigment cell types. These interactions are mediated by channels involved in direct cell contact between the pigment cells, as well as unknown cues provided by the tissue environment.     

Human skin reconstruct models: a new application for studies of melanocyte and melanoma biology

Studies of melanocyte and melanoma biology using monocultures of cells are limited because of culture-induced morphology changes and expression of genes related to growth, migration, and invasion, which do not reflect the in situ phenotype of normal melanocytes, nevus cells, or melanoma cells from biologically early progression stages. The development of organotypic cultures of human skin, in which culture artifacts are greatly diminished and cell-matrix and cell-cell interactions between different cell types can be investigated in a three-dimensional system, has opened a new era for melanoma research. Long-term in vivo studies, especially important for melanomagenesis and melanoma metastasis have become possible through grafting of skin reconstructs to immunodeficient laboratory animals. In this review, principles and different methods of skin reconstruction are introduced with focus on the application for pigment cell biology.     

Dendritic cells in the skin – potential use for melanoma treatment

Melanoma is an aggressive malignancy with poor prognosis. Eradication of tumor cells requires an effective interaction between melanoma cells and different players of the immune system. As the most potent professional antigen‐presenting cells, dendritic cells (DCs) play a pivotal role in mounting a specific immune response where their intratumoral and peritumoral density as well as their functional status are correlated with clinical staging of the disease and with patients’ survival. Under steady‐state conditions, internalization of apoptotic cells by immature DCs designates a state of tolerance to self‐antigens. Nevertheless, pathogens and necrotic cells interacting with pattern recognition receptors trigger downstream signaling pathways that evoke maturation of DCs, leading to the production of pro‐inflammatory cytokines. These mature DCs are essential for T‐cell priming and subsequent development of a specific immune response. Altered functions of DCs have an impact on the development of various disorders including autoimmune diseases and cancers. Herein, we focus on the checkpoints created throughout DCs antigen capturing and presentation to T cells, with subsequent development of either tolerance or immune response, with an emphasis on the role played by DCs in melanoma tumorigenesis and their therapeutic potential.     

c-Met is essential for wound healing in the skin

Wound healing of the skin is a crucial regenerative process in adult mammals. We examined wound healing in conditional mutant mice, in which the c-Met gene that encodes the receptor of hepatocyte growth factor/scatter factor was mutated in the epidermis by cre recombinase. c-Met-deficient keratinocytes were unable to contribute to the reepithelialization of skin wounds. In conditional c-Met mutant mice, wound closure was slightly attenuated, but occurred exclusively by a few (5%) keratinocytes that had escaped recombination. This demonstrates that the wound process selected and amplified residual cells that express a functional c-Met receptor. We also cultured primary keratinocytes from the skin of conditional c-Met mutant mice and examined them in scratch wound assays. Again, closure of scratch wounds occurred by the few remaining c-Met-positive cells. Our data show that c-Met signaling not only controls cell growth and migration during embryogenesis but is also essential for the generation of the hyperproliferative epithelium in skin wounds, and thus for a fundamental regenerative process in the adult.