Pigment Cell & Melanoma Research[JOURNAL]
Sun
155 papers
Antitumoral, antioxidant, and antimelanogenesis potencies of Hawthorn, a potential natural agent in the treatment of melanoma.
Mustapha N, Mokdad-Bzéouich I, Maatouk M … +3 more , Ghedira K, Hennebelle T, Chekir-Ghedira L
Melanoma Res · 2016 Jun · PMID 26795272 · Publisher ↗
The lack of an efficient agent that does not have the disadvantage of low activity (kojic acid), high cytotoxicity, and mutagenicity (hydroquinone), poor skin penetration (arbutin), or low stability in formulation (glabr...
The lack of an efficient agent that does not have the disadvantage of low activity (kojic acid), high cytotoxicity, and mutagenicity (hydroquinone), poor skin penetration (arbutin), or low stability in formulation (glabridin) led us to continue our research on new antipigmentation/skin-lightening agents. Therefore, research of natural products that can modulate the metabolism of pigmentation is of great interest. Otherwise, malignant melanoma is one of the most aggressive forms of skin cancer, with high metastatic potential, and currently, there is no effective chemotherapy against invasive melanoma. Therefore, it is necessary to develop new drugs with potent activity and weak side effects against melanoma. The in-vitro anticancer effect of hawthorn was analyzed against B16F10 melanoma cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effect of isolated compounds from hawthorn on melanogenesis in B16F10 melanoma cells was investigated by measuring the amounts of melanin and tyrosinase spectrophotometrically at 475 nm. Balb/c mice models inoculated with B16F10 mouse tumor cells were used to evaluate the in-vivo antitumoral potential of hawthorn by assessing its effect on the growth of transplanted tumors. The antioxidant potential of tested samples was evaluated in B16F10 and primary human keratinocyte cells using a cellular antioxidant activity assay. Hawthorn tested samples inhibited effectively the growth of melanoma cells in vitro. Furthermore, it appears that tested samples from hawthorn reduced melanogenesis by inhibiting the tyrosinase activity of B16F10 cells in a dose-dependent manner. In-vivo studies showed that hawthorn total oligomer flavonoids extract treatment at a dose of 150 mg/kg body weight for 21 days in implanted tumor mice resulted in significant inhibition of the tumor growth volume and weight. In addition, tested samples showed significant cellular antioxidant capacity against the reactive oxygen species in B16F10 and primary human keratinocyte cells. Our results indicate that hawthorn could be considered as a promising agent for the treatment of melanoma as it shows antitumor activity in vitro and in vivo. Moreover, hawthorn constituents are shown to be highly effective at inhibiting tyrosinase-mediated melanogenesis in vitro on melanoma cells by preventing oxidation in these cells and without affecting the viability of normal human keratinocyte cells. Then, hawthorn might also be used as a new candidate of natural skin depigmenting agents in skin care products.
Identification of a small molecule that downregulates MITF expression and mediates antimelanoma activity in vitro.
Cheng C, Yang HW, Shang JF … +6 more , Li WW, Sun QZ, Chen X, Cao ZX, Yao SH, Yang SY
Melanoma Res · 2016 Apr · PMID 26684062 · Publisher ↗
Melanoma is a type of cancer arising from the melanocytes, which are the cells that make up the pigment melanin and are derived from the neural crest. There is no particularly effective therapy once the disease is metast...
Melanoma is a type of cancer arising from the melanocytes, which are the cells that make up the pigment melanin and are derived from the neural crest. There is no particularly effective therapy once the disease is metastatic, highlighting the need for discovery of novel potent agents. In this investigation, we adopted a zebrafish embryonic pigmentation model to identify antimelanoma agents by screening an in-house small molecule library. With this assay, we found that a small molecule compound, SKLB226, blocked zebrafish pigmentation and pigment cell migration. Mechanism of action studies showed that SKLB226 downregulated MITF mRNA level in both zebrafish embryos and mammalian melanoma cells. Further studies showed that it could efficiently suppress the viability and migration of mammalian melanoma cells. In summary, SKLB226 can be used as a chemical tool to study melanocyte development as well as an antimelanoma lead compound that should be subjected to further structural optimization.
Haplosufficiency of PAX3 for melanoma development in Tyr: NRASQ61K; Cdkn2a-/- mice allows identification and sorting of melanoma cells using a Pax3GFP reporter allele.
Campagne C, Reyes-Gomez E, Loiodice S … +9 more , Gadin S, Ezagal J, Bernex F, Abitbol M, Louise A, Beermann F, Panthier JJ, Aubin-Houzelstein G, Egidy G
Melanoma Res · 2016 Feb · PMID 26587692 · Publisher ↗
The role of the Pax3 gene in embryonic development of pigment cells is well characterized. By contrast, the function of Pax3 in melanoma development is controversial. Indeed, data obtained from cultured cells suggest tha...
The role of the Pax3 gene in embryonic development of pigment cells is well characterized. By contrast, the function of Pax3 in melanoma development is controversial. Indeed, data obtained from cultured cells suggest that PAX3 may contribute to melanomagenesis. PAX3 is found to be overexpressed in melanomas and also in nevi compared with normal skin samples. Pax3 homozygous loss of function is embryonic lethal. To assess the role of Pax3 in melanoma development in vivo, we analyzed Pax3 haploinsufficiency in a mouse model of melanoma predisposition. The Pax3(GFP/+) knock-in reporter system was combined with the Tyr::NRAS(Q61K); Cdkn2a(-/-) mouse melanoma model. Melanoma development was followed over 18 months. Histopathological, immunohistochemical, and molecular analyses of lesions at different stages of melanoma progression were carried out. Fluorescence-activated cell sorting on GFP of cells from primary or metastatic melanoma was followed by ex-vivo transformation tests and in-vivo passaging. We report here that Tyr::NRAS(Q61K); Cdkn2a(-/-); Pax3(GFP/+) mice developed metastasizing melanoma as their Tyr::NRAS(Q61K); Cdkn2a(-/-); littermates. Histopathology showed no differences between the two genotypes, although Pax3 mRNA and PAX3 protein levels in Pax3(GFP/+) lesions were reduced by half. The Pax3(GFP) allele proved to be a convenient marker to identify and directly sort heterogeneous populations of melanoma cells within the tumor bulk at each stage of melanoma progression. This new mouse model represents an accurate and reproducible means for identifying melanoma cells in vivo to study the mechanisms of melanoma development.
Amplification of mutated NRAS leading to congenital melanoma in neurocutaneous melanocytosis.
Salgado CM, Basu D, Nikiforova M … +6 more , Hamilton RL, Gehris R, Jakacki R, Panigrahy A, Yatsenko S, Reyes-Múgica M
Melanoma Res · 2015 Oct · PMID 26266759 · Publisher ↗
The mechanisms behind malignant progression in patients with giant nevi are largely unknown. Here, we aim to describe novel genetic findings and explain possible mechanisms resulting in the most severe form of neurocutan...
The mechanisms behind malignant progression in patients with giant nevi are largely unknown. Here, we aim to describe novel genetic findings and explain possible mechanisms resulting in the most severe form of neurocutaneous melanocytosis. Detailed histological (biopsy and post-mortem) studies, tissue culture, and high-resolution cytogenetic analysis, including chromosome and array comparative genomic hybridization, Ion AmpliSeq Cancer Panel, and Sanger sequencing, were performed on tissues from a white male who succumbed at 17 months of age to congenital melanoma associated with a bathing-trunk nevus. We also used quantitative PCR to quantitatively assess the expression of NRAS among normal cells, including fibroblast and melanocytes, as well as melanoma cells from our patient. Full autopsy documented tumors in the brain, spinal cord, lung, liver, testis, bone marrow, and, retrospectively, in the placenta. Next-generation sequencing and chromosome microarray in our patient revealed novel findings, including duplication of a mutated NRAS gene, leading to an aggressive clinical course and disseminated disease. Quantitative PCR showed a five-fold increase in NRAS expression in the melanoma cell line when compared with normal melanocytes. Finally, three amino acid-changing germline variants were detected: homozygous TP53 p.P72R, heterozygous KIT p.M541L, and homozygous KDR (VEGFR2) p.Q472H. These genes are involved in malignancy and other potentially relevant pathways, such as mast cell and melanocytic signaling, as well as angiogenesis. These findings provide novel insights into the biology of congenital melanocytic proliferations, showing that amplification of mutated NRAS seems to represent a new genetic mechanism leading to melanoma in the context of neurocutaneous melanocytosis.
Eruptive naevi in a patient treated with LGX818 for BRAF mutant metastatic melanoma.
Anforth RM, Carlos GR, Scolyer RA … +2 more , Chou S, Fernandez-Peñas P
Melanoma Res · 2015 Feb · PMID 25380183 · Publisher ↗
LGX818 is a new-generation BRAF inhibitor (BRAFi) that is currently undergoing phase 3 trials for the treatment of BRAF mutant metastatic melanoma patients (NCT01909453). Cutaneous toxicities associated with the administ...
LGX818 is a new-generation BRAF inhibitor (BRAFi) that is currently undergoing phase 3 trials for the treatment of BRAF mutant metastatic melanoma patients (NCT01909453). Cutaneous toxicities associated with the administration of BRAF inhibitors are considered to be induced by the paradoxical activation of the mitogen-activated protein kinase pathway in wild-type BRAF cells. Changes in naevi, including new naevi, hyperpigmentation and fading of existing naevi, have also been reported. In addition, some patients receiving these therapies have developed second primary melanomas. As a consequence, the importance of sequential digital dermoscopy in all patients treated with a BRAFi to detect new primary melanomas has been emphasized. A 61-year-old man with BRAF mutant stage IV metastatic melanoma was commenced on the phase 1 trial of LGX818 at 300 mg daily in 2013. After 2 months of therapy, the patient was noted to have developed eruptive naevi, fading of existing naevi and darkening of other naevi. Excision of a new pigmented lesion from the back indicated a compound naevus. Immunohistochemistry showed that the naevus cells lacked a BRAF V600E mutation. This is the first reported case of eruptive naevi in a patient treated with LGX818. The absence of the BRAF V600E mutation within a changing naevus supports the theory that BRAFi stimulates the proliferation of wild-type BRAF cells. Close dermatological surveillance is important for all patients treated with any type of BRAFi.
Value of dopachrome tautomerase detection in the assessment of melanocytic tumors.
Filimon A, Zurac SA, Milac AL … +3 more , Sima LE, Petrescu SM, Negroiu G
Melanoma Res · 2014 Jun · PMID 24709887 · Publisher ↗
Dopachrome tautomerase (DCT) and tyrosinase (Tyr) are melanogenic enzymes and structurally related melanosomal proteins. The present study investigates DCT expression comparatively with Tyr, the most tested melanoma biom...
Dopachrome tautomerase (DCT) and tyrosinase (Tyr) are melanogenic enzymes and structurally related melanosomal proteins. The present study investigates DCT expression comparatively with Tyr, the most tested melanoma biomarker, aiming to evaluate DCT potential in the assessment of melanocytic tumors and gain insights into the molecular and pathological characterization of DCT-phenotype in tumor progression. DCT and Tyr are simultaneously analyzed in melanoma cell lines by semiquantitative RT-PCR, western blot, and N-glycan analysis, and in cell populations of melanocytic tumors by immunohistofluorescence using a novel anti-hDCT antibody against an extended sequence within DCT luminal domain. DCT, unlike Tyr, is fully processed along the secretory pathway in both pigmented and amelanotic melanoma cells. In 53 nevi and 116 primary malignant melanomas, 81% and 52%, respectively, are DCT+/Tyr+, showing that DCT is a stable antigen, retained by most tumors and partially expressed in Tyr-negative cell populations. The DCT/Tyr disjunction is a process correlated with melanocyte neoplastic transformation and malignant progression. A tumor architecture--DCT-phenotype-containing DCT+/Tyr- cell populations selected into the innermost dermis from double-positive cells is detected in 35% of DCT+/Tyr+ specimens. The DCT-phenotype is associated with enhanced neurotization in benign nevi and with ulceration in thin malignant melanomas. The intradermal DCT+/Tyr- clones in superficial melanomas acquire the expression and specific subcellular distribution of unfavorable prognostic markers. DCT assessment shows specific antigen patterns with potential significance in the outcome of melanocytic lesions, connecting DCT, a mediator of a melanoma stress-resistant pathway, and an antiapoptotic molecule to DCT- phenotypes that are possibly more stable and stress resistant.
Chemoprevention of skin melanoma: facts and myths.
Uzarska M, Czajkowski R, Schwartz RA … +3 more , Bajek A, Zegarska B, Drewa T
Melanoma Res · 2013 Dec · PMID 24077511 · Publisher ↗
Melanoma is the most dangerous type of skin cancer. Despite the rise of public awareness, the incidence rate among the white population has been rising constantly for several decades. Systematic improvement in knowledge...
Melanoma is the most dangerous type of skin cancer. Despite the rise of public awareness, the incidence rate among the white population has been rising constantly for several decades. Systematic improvement in knowledge about the biology of pigment cells and molecular mechanisms of their neoplastic transformation has enhanced the possibility of melanoma chemoprevention. Hence, chemopreventive agents that prevent, inhibit, or reverse melanoma development are being investigated intensively. Among synthetic compounds, especially well studied are lipid-lowering drugs and cyclooxygenase inhibitors. Substances found in everyday diet, such as genistein, apigenin, quercetin, resveratrol, and curcumin may also have potential chemopreventive qualities. However, studies examining the chemopreventive activity of these compounds have shown widely varying results. Early reports on the possible chemopreventive activity of statins and fibrates were not proved by the results of randomized clinical trials. Similarly, case-control studies examining the influence of NSAIDs on the risk of melanoma do not confirm the antitumor activity of cyclooxygenase inhibitors. Further clinical trials involving carefully selected target populations as well as the identification of specific biomarkers of prognostic and predictive value seem to be essential for the evaluation of the chemopreventive activity of the studied substances.
Polymorphisms in the p27kip-1 and prohibitin genes denote novel genes associated with melanoma risk in Brazil, a high ultraviolet index region.
Francisco G, Gonçalves FT, Luiz OC … +12 more , Saito RF, Toledo RA, Sekiya T, Tortelli TC, Violla ED, Furuya Mazzotti TK, Cirilo PD, Festa-Neto C, Sanches JA, Gattás GJ, Eluf-Neto J, Chammas R
Melanoma Res · 2013 Jun · PMID 23624368 · Publisher ↗
Ultraviolet (UV) radiation is a major environmental risk factor to the development of cutaneous melanoma as it induces pyrimidine dimers in DNA. Genes that exert their function by arresting the cell cycle are critical to...
Ultraviolet (UV) radiation is a major environmental risk factor to the development of cutaneous melanoma as it induces pyrimidine dimers in DNA. Genes that exert their function by arresting the cell cycle are critical to avoid carcinogenic mutations, allowing the processing of DNA repair systems. This study was carried out to evaluate the role of polymorphisms in cell cycle genes such as TP53, p27, CDKN2A, prohibitin, and GADD153 in melanoma risk as well as their influence on known risk factors in a high UV index region. A hospital-based case-control study was carried out in Brazil to evaluate the contribution of polymorphisms in cell cycle genes toward melanoma risk. The study comprised 202 melanoma patients and 210 controls. The polymorphisms analyzed were TP53 Arg72Pro, p27 Val109Gly, GADD153 Phe10Phe (rs697221), CDKN2A 3'UTR C540G, and prohibitin 3'UTR C1703T. As regards, p27 Val109Gly, both heterozygous and homozygous Gly genotypes were shown to be protective genotypes on calculating both crude and adjusted odds ratios (ORs) for age, sex, and educational level [OR 0.37; 95% confidence interval (CI) 0.16-0.87; P<0.05]. Similarly, the prohibitin TT genotype increased melanoma risk in the crude and adjusted analyses (OR 2.40; 95% CI 1.10-5.26; P<0.05). The p27 Gly protective genotype decreased the risk for melanoma in a stratified analysis of the known risk factors such as hair and eye color, sunburns, pigmented lesions, and European ancestry. The prohibitin TT genotype increased the risk of melanoma by such host factors. Our results showed for the first time that polymorphisms in p27 Val109Gly and in prohibitin 3'UTR C1703T genotypes modulate the risk to melanoma in a high UV index region.
Can noninvasive imaging tools potentially predict the risk of ulceration in invasive melanomas showing blue and black colors?
Longo C, Farnetani F, Moscarella E … +10 more , de Pace B, Ciardo S, Ponti G, Piana S, Cesinaro AM, Cota C, Argenziano G, Rosendahl C, Pellacani G, Zalaudek I
Melanoma Res · 2013 Apr · PMID 23358425 · Publisher ↗
The aim of this study was to evaluate the reflectance microscopy and histopathologic correlates of dermoscopic blue and black color (BB) in a series of melanomas. We searched our database for dermoscopic images of histop...
The aim of this study was to evaluate the reflectance microscopy and histopathologic correlates of dermoscopic blue and black color (BB) in a series of melanomas. We searched our database for dermoscopic images of histopathologically diagnosed pigmented nodular melanomas (pNM), superficial spreading melanomas with a nodular component (SSM+Nod), and melanoma metastasis (METs). All cases were assessed for the presence of dermoscopic BB. Confocal microscopy findings were then compared with those of histopathology. A total of 17 BB-positive tumors including eight pNMs, five SSM+Nod, and four METs were included in the study. We identified two different dermoscopic patterns associated with black color, namely, large black blotches and irregular black dots/globules, which corresponded to two different confocal and histopathologic findings. Black blotches resulted from a total filling of the epidermis by an upward migration of melanocyte nests and pagetoid melanocytes as single cells and clusters, whereas black dots/globules also corresponded to the upward migration of melanocyte nests in the epidermis and pagetoid spread, but with sparing of intervening areas of epidermis. Interestingly, two pNM and two METs showing black color lacked any epidermal involvement and, instead, they were characterized by upward-bulging dermal masses of atypical melanocytes covered by an highly attenuated epidermis. In both cases, black color corresponded to pigment-containing melanocytes in close proximity to the surface of the skin. Our study suggests that black color results not only from epidermal melanin but also from a dense dermal proliferation of pigmented melanocytes under a thinned epidermis. It seems reasonable to suggest that a bulging proliferation of dermal melanocytes beneath a thin epidermal layer could precede ulceration. As ulceration is a very significant prognostic factor, speculation arising from this study that dermoscopic black color may in some cases indicate incipient ulceration is worthy of further study.
LINE-1 methylation in peripheral blood and the risk of melanoma in melanoma-prone families with and without CDKN2A mutations.
Hyland PL, Burke LS, Pfeiffer RM … +4 more , Mirabello L, Tucker MA, Goldstein AM, Yang XR
Melanoma Res · 2013 Feb · PMID 23222549 · Full text
Cutaneous malignant melanoma (CMM) is an etiologically heterogenous disease with genetic, environmental (sun exposure), and host (pigmentation/nevi) factors and their interactions contributing to risk. Recently, epigenet...
Cutaneous malignant melanoma (CMM) is an etiologically heterogenous disease with genetic, environmental (sun exposure), and host (pigmentation/nevi) factors and their interactions contributing to risk. Recently, epigenetic changes involving reduced levels of global DNA methylation in blood have been associated with genomic instability and cancer risk. We thus examined whether global methylation was associated with CMM risk in individuals from melanoma-prone families with and without CDKN2A germline mutations. We measured global DNA methylation using bisulfite pyrosequencing at four CpG sites of the long interspersed nucleotide element-1 (LINE-1) sequences in peripheral blood mononuclear cells (PBMCs) from individuals in 64 melanoma-prone families including 114 CMM cases (45 CDKN2A-positive and 69 CDKN2A-negative) and 121 unaffected individuals (31 CDKN2A-positive and 90 CDKN2A-negative). We used unconditional logistic regression to evaluate the association between CMM status and LINE-1 methylation levels, adjusting for age at blood draw and accounting for familial correlation in the variance. We found that male sex was significantly associated with higher overall LINE-1 methylation (P=0.0001). However, the overall and site-specific levels of LINE-1 methylation did not vary significantly by CMM status (overall odds ratio: 1.57, 95% confidence interval: 0.84-2.95, P=0.16; comparing lowest to highest or reference methylation group). Similar results were obtained when CDKN2A-positive and CDKN2A-negative families were analyzed separately. Our findings did not support a significant association between constitutional LINE-1 methylation in PBMCs and risk of CMM in melanoma-prone families with or without CDKN2A mutations.
Features of small melanocytic lesions: does small mean benign? A clinical-dermoscopic study.
de Giorgi V, Savarese I, Rossari S … +6 more , Gori A, Grazzini M, Crocetti E, Sara Longo A, Oranges T, Massi D
Melanoma Res · 2012 Jun · PMID 22430838 · Publisher ↗
The use of dermoscopy is known to increase the sensitivity and specificity in the clinical diagnosis of cutaneous pigmented melanocytic lesions compared with naked-eye examinations. However, small pigmented melanocytic l...
The use of dermoscopy is known to increase the sensitivity and specificity in the clinical diagnosis of cutaneous pigmented melanocytic lesions compared with naked-eye examinations. However, small pigmented melanocytic lesions with maximum clinical diameters of 6 mm remain the most significant diagnostic challenge to the clinician, particularly in the diagnosis of small melanoma, both in naked-eye and in dermatoscopic examinations. The aim of the present study was to analyze the clinical and dermatoscopic features of small pigmented melanocytic lesions, focusing on more frequently occurring features in small melanoma to identify them earlier. A total of 103 pigmented melanocytic lesions with diameters less than 6 mm were analyzed. On histopathological examination, 34 of these lesions were diagnosed as melanomas and the remaining lesions (n = 69) were diagnosed as benign, melanocytic lesions. Images of cases were independently and blindly administered to three dermatologist experts in dermoscopy, who were asked to examine the clinical and dermatoscopic images of melanocytic skin lesions separately and to fill out a printed questionnaire to rate the images according to the ABCD clinical criteria and according to typical dermoscopic pattern analyses. The results of the questionnaires were then analyzed and crossed in order to rate the clinical and dermoscopic features of small pigmented lesions. Our study proved that the clinical criteria for diagnosing melanoma are not as reliable in the diagnosis of pigmented lesions of less than 6 mm diameter. However, the use of dermoscopy, even if not nullifying, allows a better classification of small, melanocytic lesions through pattern analysis.
Study of c-kit immunoexpression in canine cutaneous melanocytic tumors.
Gomes J, Queiroga FL, Prada J … +1 more , Pires I
Melanoma Res · 2012 Jun · PMID 22407004 · Publisher ↗
Melanocytic tumors occur as much in humans as in dogs and are frequently associated with receptor tyrosine kinase dysregulation. The transmembrane c-kit protein is a receptor tyrosine kinase that is crucial in melanocyti...
Melanocytic tumors occur as much in humans as in dogs and are frequently associated with receptor tyrosine kinase dysregulation. The transmembrane c-kit protein is a receptor tyrosine kinase that is crucial in melanocytic homeostasis and, when mutated, is associated with tumor development in those cells. In human studies, its expression is generally detected in melanocytomas and primary malignant melanomas, being lost with tumor progression and metastasis. In this study, we aimed to analyze c-kit expression in canine cutaneous melanocytic tumors and its association with tumor behavior, in order to investigate the dog's potential in comparative pathology and c-kit's potential in the diagnosis of these tumors. The expression of c-kit was evaluated immunohistochemically in 39 canine cutaneous melanocytic tumors and scored in terms of the labeling location, extension, and intensity. The labeling location was essentially cytoplasmic, and the labeling extension and intensity were generally higher in melanocytomas (83.3% diffuse-labeled cells) than those in malignant melanomas (22.2% negative-labeled cells). The differences found in the labeling extension were statistically significant (P < 0.001). There was no association between c-kit immunoexpression in malignant melanomas and the clinicopathological criteria, except between the labeling intensity and the degree of intralesional pigmentation (P = 0.048). Our results for labeling extension are in agreement with similar human studies, reinforcing the dog's potential as a model organism for investigation in this type of cancer. In addition, the loss of c-kit expression in malignant melanomas might be a criterion of tumor aggressiveness, indicating that this receptor may be useful in the diagnosis of these tumors.
MicroRNA regulation of melanoma progression.
Bonazzi VF, Stark MS, Hayward NK
Melanoma Res · 2012 Apr · PMID 22209751 · Publisher ↗
The aetiology of melanoma, the most lethal form of skin cancer, is complex, involving both genetic and environmental components. Over the past decade, many genetic alterations affecting melanoma development have been ide...
The aetiology of melanoma, the most lethal form of skin cancer, is complex, involving both genetic and environmental components. Over the past decade, many genetic alterations affecting melanoma development have been identified and more recently a new epigenetic level of regulation has increasingly been explored. MicroRNA (miRNA)-mediated epigenetic regulation of tumour suppressor genes and oncogenes has been shown to play a central role in melanomagenesis. Over the past few years, many studies combining miRNA expression arrays and quantitative reverse transcriptase-PCR assays have identified different miRNAs deregulated during melanoma progression. Several groups have focused their efforts on understanding the functional role of these different miRNAs in melanoma, identifying their direct targets and elucidating their mechanisms of regulation. This review summarizes the present knowledge of miRNA dysregulation in melanoma. On the basis of the current literature, we present a network of miRNA interactions involved in melanoma progression. Some of these key miRNAs may have utility as diagnostic markers or in targeted treatments.
Expression of CD133 and other putative stem cell markers in uveal melanoma.
Thill M, Berna MJ, Grierson R … +8 more , Reinhart I, Voelkel T, Piechaczek C, Galambos P, Jager MJ, Richard G, Lange C, Gehling UM
Melanoma Res · 2011 Oct · PMID 21900792 · Publisher ↗
'Cancer stem cells' (CSCs) are tumor cells with stem cell properties hypothesized to be responsible for tumorigenesis, metastatis, and resistance to treatment, and have been identified in different tumors including cutan...
'Cancer stem cells' (CSCs) are tumor cells with stem cell properties hypothesized to be responsible for tumorigenesis, metastatis, and resistance to treatment, and have been identified in different tumors including cutaneous melanoma, using stem cell markers such as CD133. This study explored expression of CD133 and other putative stem cell markers in uveal melanoma. Eight uveal melanoma cell lines were subjected to flow-cytometric (fluorescence-activated cell sorting) analysis of CD133 and other stem cell markers. Eight paraffin-embedded tumors were analyzed by immunohistochemistry for CD133, Pax6, Musashi, nestin, Sox2, ABCB5, and CD68 expressions. Ocular, uveal melanoma, and hematopoietic stem cell distributions of C-terminal and N-terminal CD133 mRNA splice variants were compared by reverse-transcription PCR. Fluorescence-activated cell sorting analysis revealed a population of CD133-positive/nestin-positive cells in cell lines Mel270, OMM 2.3, and OMM2.5. All cell lines studied were positive for nestin, CXCR-4, CD44, and c-kit. Immunohistochemistry identified cells positive for CD133, Pax6, Musashi, nestin, Sox2, ABCB5, and CD68 predominantly at the invading tumor front. C-terminal primers interacting with CD133 splice variant s2 detected a novel variant lacking exon 27. Differential expression of CD133 splice variants was found in iris, ciliary body, retina, and retinal pigment epithelium/choroid as well as in uveal melanoma cell lines. mRNA for nestin, Sox2, and Musashi was present in all studied cell lines. Uveal melanoma such as cutaneous melanoma may therefore contain CSCs. Further experiments are needed to isolate stem cell marker-positive cells, to evaluate their functional properties and to explore therapeutical approaches to these putative CSCs in uveal melanoma.
Changes in the gene expression profile of A375 human melanoma cells induced by overexpression of multifunctional pigment epithelium-derived factor.
Orgaz JL, Benguria A, Sanchez-Martinez C … +3 more , Ladhani O, Volpert OV, Jimenez B
Melanoma Res · 2011 Aug · PMID 21673604 · Full text
Pigment epithelium-derived factor (PEDF) is a broad-spectrum angiogenesis inhibitor that displays potent antimetastatic activity in multiple tumor types. We have previously shown that PEDF prevents primary tumor growth a...
Pigment epithelium-derived factor (PEDF) is a broad-spectrum angiogenesis inhibitor that displays potent antimetastatic activity in multiple tumor types. We have previously shown that PEDF prevents primary tumor growth and metastatic spread of human melanoma in mouse experimental models. Consistent with these observations, PEDF expression is lost at the late stages of melanoma progression, allowing melanoma cells to become angiogenic, migratory, and invasive. PEDF's ability to modify the interplay between the host and tumor tissues strongly supports its use as a therapeutic agent for the treatment of metastatic melanoma. However, transition to the clinic requires a more detailed knowledge of the molecular mechanisms underpinning PEDF's activity. In this study, we describe changes in the gene expression profile of A375 human melanoma cells induced by PEDF overexpression. PEDF modulated diverse categories of genes known to be involved in angiogenesis and migration. It downregulated cytokines such as interleukin-8 and extracellular matrix proteins such as collagen IV, while it upregulated fibronectin. Multiple transcripts previously described as contributing to the acquisition of malignant phenotype by melanoma were also diminished by PEDF overexpression, among which we validated galectin 3 and jagged 1. In addition, PEDF downregulated S100β and melanoma inhibitory activity, which are widely used in the pathological diagnosis of melanoma. Interestingly, PEDF increased the expression of melanophilin and decreased rab27A, which are relevant targets for melanosome transport; suggesting that PEDF could directly impinge on melanocytic lineage-specific processes. Our study identifies new molecular targets and signaling pathways that may potentially contribute to determine PEDF's ability to restrict the aggressiveness of A375 human melanoma cells.
Topical application of bleaching phenols; in-vivo studies and mechanism of action relevant to melanoma treatment.
Hariharan V, Toole T, Klarquist J … +3 more , Mosenson J, Longley BJ, Le Poole IC
Melanoma Res · 2011 Apr · PMID 21317816 · Full text
Skin depigmentation represents a well-established treatment for extensive vitiligo and may likewise be suited to prevent tumor recurrences and as a prophylactic treatment of familial melanoma, as common bleaching agents...
Skin depigmentation represents a well-established treatment for extensive vitiligo and may likewise be suited to prevent tumor recurrences and as a prophylactic treatment of familial melanoma, as common bleaching agents are cytotoxic to melanocytes. Effective melanoma prevention requires a bleaching agent-induced loss of exposed melanocytes supported by an immune response to distant pigment cells. Studies on human explant cultures treated with depigmenting agents such as 4-tertiary butyl phenol (4-TBP) or monobenzyl ether of hydroquinone (MBEH) showed a significant increase in the migration of Langerhans cells toward the dermis only upon treatment with MBEH, thus suggesting selective elicitation of an immune response. To assess the depigmenting potential of bleaching agents in vivo, 4-TBP and MBEH were topically applied to C57BL/6 wild type as well as k14-SCF transgenic, epidermally pigmented mice. MBEH-induced significant skin depigmentation in both strains was not observed upon treatment with 4-TBP. Cytokine expression patterns in skin treated with MBEH support activation of a Th1-mediated immune response corresponding to an influx of T cells and macrophages. Importantly, despite insensitivity of tumor cells to MBEH-induced cytotoxicity, significantly retarded tumor growth was observed in B16 challenged k14-SCF mice pretreated with MBEH, likely due to an abundance of cytotoxic T cells accompanied by an increased expression of Th1 and Th17 cytokines. These data support the use of MBEH as a prophylactic treatment for melanoma.
Melanoma of unknown primary site: a 33-year experience at the Turin Melanoma Centre.
Savoia P, Fava P, Osella-Abate S … +4 more , Nardò T, Comessatti A, Quaglino P, Bernengo MG
Melanoma Res · 2010 Jun · PMID 20449885
Unknown melanoma occurs as metastasis to skin, nodes or viscera, without a detectable cutaneous primary tumour. We reviewed our database of 4881 melanoma patients, diagnosed and followed up prospectively for a 33-year pe...
Unknown melanoma occurs as metastasis to skin, nodes or viscera, without a detectable cutaneous primary tumour. We reviewed our database of 4881 melanoma patients, diagnosed and followed up prospectively for a 33-year period. We identified 93 cases of metastatic melanoma without evidence of primary; however, five of these patients had a history of a previous excision of a presumed benign lesion without histological examination and were excluded from analyses. At diagnosis, metastases were cutaneous in 35.3% of cases, nodal in 43.2% and visceral in 17% of cases; in 4.5% of patients, both skin and nodes were involved. In all cases, clinical inspection and staging procedures performed at diagnosis of metastatic disease failed to identify a primary melanoma. In 11 cases (11.8%), extensively regressed pigmented lesions (without evidence of melanoma cells at the histological examination) were documented; moreover, we identified in our series five patients with unknown primary affected by vitiligo. The 5-year and 10-year overall survival rates were 49.6 and 41.4%, respectively, with a median of 4.9 years. The 5-year and 10-year time to progression rates were 39.4 and 32.3%, respectively, with a median of 2.3 years. Survival was longer in females and showed significant differences among patients with skin, lymph node or visceral involvement at diagnosis. In melanoma patients, unknown primary represents a not so rare event, with an uncertain origin. We confirmed the relatively good prognosis of unknown primary melanoma patients, a fact that has to be taken into consideration for their management.
Expression patterns of S100 proteins in melanocytes and melanocytic lesions.
Petersson S, Shubbar E, Enerbäck L … +1 more , Enerbäck C
Melanoma Res · 2009 Aug · PMID 19521263 · Publisher ↗
S100 proteins are differentially expressed in tumours of epithelial origin. Little is known about their expression in melanocyte-derived tumours of neuroectodermal origin. We have analysed the expression of some S100 pro...
S100 proteins are differentially expressed in tumours of epithelial origin. Little is known about their expression in melanocyte-derived tumours of neuroectodermal origin. We have analysed the expression of some S100 proteins in this line of lesions using SAGE Genie informatics, cell culture and human tumour tissue. The pattern of expression of six S100 proteins was investigated at both the mRNA and protein levels, using quantitative real-time PCR, western blotting and immunohistochemical analysis. No differential expression was observed with respect to S100A4, S100A7, S100A8, S100A9 and S100A11. In contrast, S100A10 was downregulated in three melanoma cell lines compared with normal melanocytes. Using SAGE informatics, two-dimensional displays of microarray expression data from the NCI60_Novartis cell lines displayed a positive correlation between the expression of S100A10 and the expression of the proliferation marker, Ki67. Our data suggest that S100A10, like its binding partners S100A7 and annexin A2, is an oxidant-sensitive protein. In addition, higher expression of S100A10 was detected in melanocyte cell lines with long projections compared with melanoma cell lines with small ripples. In a panel of 47 melanocyte-derived lesions comprising melanocytic naevi and melanomas, S100A10 was expressed to varying degrees in the melanocytic lesions. The antigen was primarily expressed in regions with a strong proliferating or differentiating capacity, especially in regions in or near the epidermis. We suggest that S100A10 may play a role in the regulation of the proliferation or early maturation sequence of melanocytic lesions, and that it merits further study as a potential biomarker of activity.
Comparison of eumelanin and pheomelanin content between cultured uveal melanoma cells and normal uveal melanocytes.
Hu DN, Wakamatsu K, Ito S … +1 more , McCormick SA
Melanoma Res · 2009 Apr · PMID 19262410 · Publisher ↗
Levels of eumelanin (EM) and pheomelanin (PM) of uveal melanoma cells have not been measured and compared with those of normal uveal melanocytes. EM and PM amounts in four immortal human uveal melanoma cell lines were me...
Levels of eumelanin (EM) and pheomelanin (PM) of uveal melanoma cells have not been measured and compared with those of normal uveal melanocytes. EM and PM amounts in four immortal human uveal melanoma cell lines were measured by chemical degradation and microanalytical high-performance liquid chromatography and compared with those from 39 normal human uveal melanocyte cell lines reported earlier by us. Uveal melanoma cells had a very low EM/PM ratio (0.41), which was very significantly lower than that from normal melanocytes isolated both from eyes with light-colored irides (1.31) or dark-colored irides (7.32). The low EM/PM ratio was caused by a low level of EM in melanoma cells, which was only 1/8 and 1/31 of that in melanocytes from eyes with light-colored irides and dark-colored irides, respectively. The PM level in uveal melanoma cells was not statistically different from normal melanocytes from eyes with light-colored irides or dark-colored irides. The total quantity of EM and PM in uveal melanoma cells was significantly less than that in normal melanocytes. This difference was because of the low level of EM in uveal melanoma cells. The results of these studies indicate that the changes of melanin content in uveal melanoma cells mainly relate to the decrease of EM content. Low melanin and EM content may make melanoma cells more susceptible to mutagenic effects of ultraviolet radiation and oxidative stress, which may enhance the proliferation of melanoma cells and accelerate progression of melanoma.
Immunosuppression and melanocyte proliferation.
Zattra E, Fortina AB, Bordignon M … +2 more , Piaserico S, Alaibac M
Melanoma Res · 2009 Apr · PMID 19194340 · Publisher ↗
Melanocytes are pigmented cells derived from the neural crest; their proliferation is restrained by immune system. The eruption of nevi after an immunosuppressive condition is a peculiar phenomenon indicating that the im...
Melanocytes are pigmented cells derived from the neural crest; their proliferation is restrained by immune system. The eruption of nevi after an immunosuppressive condition is a peculiar phenomenon indicating that the immune system may play a major role in limiting proliferation of melanocytes. In this review, we analyze the role of immunosuppressive regimens on melanocyte proliferation. In particular, we discuss the eruptive nevi phenomenon, which is determined by the inability of the immune system to inhibit melanocyte proliferation. These clinical observations indicate that the immune system has a pivotal role in restraining melanocyte proliferation. However, although the role of the immune system in the development of nonmelanoma skin cancer has been shown clearly in several studies involving organ transplant patients, the role of immunosuppression in melanoma genesis has not yet been established. Further investigations are required to establish the real immunogenicity of melanoma, particularly in the light of the dichotomy between the eruptive nevi phenomenon in immunosuppressed patients and the low incidence of melanoma in transplanted patients.
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