Editorial

5 pages, 165 KiB

Open AccessEditorial

by Anna Fateeva and Suzie Chen

Cancers 2024, 16(5), 843; https://doi.org/10.3390/cancers16050843 - 20 Feb 2024

Viewed by 672

Melanoma only accounts for about 1% of cases in skin cancer, unlike basal cell and/or squamous cell carcinomas; however, it owes its notoriety to being the deadliest type of skin cancer [...] Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

Research

Jump to: Editorial, Review

14 pages, 4062 KiB

Open AccessArticle

Deficiency of Stabilin-1 in the Context of Hepatic Melanoma Metastasis

by Sebastian A. Wohlfeil, Ana Olsavszky, Anna Lena Irkens, Verena Häfele, Bianca Dietsch, Niklas Straub, Sergij Goerdt and Cyrill Géraud

Cancers 2024, 16(2), 441; https://doi.org/10.3390/cancers16020441 - 19 Jan 2024

Viewed by 787

Abstract

Background: This study analyzed the role of Stabilin-1 on hepatic melanoma metastasis in preclinical mouse models. Methods: In Stabilin-1^−/− mice (Stab1 KO), liver colonization of B16F10 luc2 and Wt31 melanoma was investigated. The numbers, morphology, and vascularization of hepatic metastases and the [...] Read more.

Background: This study analyzed the role of Stabilin-1 on hepatic melanoma metastasis in preclinical mouse models. Methods: In Stabilin-1^−/− mice (Stab1 KO), liver colonization of B16F10 luc2 and Wt31 melanoma was investigated. The numbers, morphology, and vascularization of hepatic metastases and the hepatic microenvironment were analyzed by immunofluorescence. Results: While hepatic metastasis of B16F10 luc2 or Wt31 melanoma was unaltered between Stab1 KO and wildtype (Ctrl) mice, metastases of B16F10 luc2 tended to be smaller in Stab1 KO. The endothelial differentiation of both types of liver metastases was similar in Stab1 KO and Ctrl. No differences in initial tumor cell adhesion and retention to the liver vasculature were detected in the B16F10 luc2 model. Analysis of the immune microenvironment revealed a trend towards higher levels of CD45⁺Gr-1⁺ cells in Stab1 KO as compared to Ctrl in the B16F10 luc2 model. Interestingly, significantly higher levels of POSTN were found in the matrix of hepatic metastases of Wt31, while liver metastases of B16F10 luc2 showed a trend towards increased deposition of RELN. Conclusions: Hepatic melanoma metastases show resistance to Stabilin-1 targeting approaches. This suggests that anti-Stab1 therapies should be considered with respect to the tumor entity or target organs. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Figure 1

19 pages, 2913 KiB

Open AccessArticle

MITF Is Regulated by Redox Signals Controlled by the Selenoprotein Thioredoxin Reductase 1

by Chelsey D. Kline, Madeleine Anderson, John W. Bassett, Gail Kent, Rachel Berryman, Matthew Honeggar, Shosuke Ito, Kazumasa Wakamatsu, Arup K. Indra, Philip J. Moos, Sancy A. Leachman and Pamela B. Cassidy

Cancers 2022, 14(20), 5011; https://doi.org/10.3390/cancers14205011 - 13 Oct 2022

Cited by 1 | Viewed by 2333

Abstract

TR1 and other selenoproteins have paradoxical effects in melanocytes and melanomas. Increasing selenoprotein activity with supplemental selenium in a mouse model of UV-induced melanoma prevents oxidative damage to melanocytes and delays melanoma tumor formation. However, TR1 itself is positively associated with progression in [...] Read more.

TR1 and other selenoproteins have paradoxical effects in melanocytes and melanomas. Increasing selenoprotein activity with supplemental selenium in a mouse model of UV-induced melanoma prevents oxidative damage to melanocytes and delays melanoma tumor formation. However, TR1 itself is positively associated with progression in human melanomas and facilitates metastasis in melanoma xenografts. Here, we report that melanocytes expressing a microRNA directed against TR1 (TR1^low) grow more slowly than control cell lines and contain significantly less melanin. This phenotype is associated with lower tyrosinase (TYR) activity and reduced transcription of tyrosinase-like protein-1 (TYRP1). Melanoma cells in which the TR1 gene (TXNRD1) was disrupted using Crispr/Cas9 showed more dramatic effects including the complete loss of the melanocyte-specific isoform of MITF; other MITF isoforms were unaffected. We provide evidence that TR1 depletion results in oxidation of MITF itself. This newly discovered mechanism for redox modification of MITF has profound implications for controlling both pigmentation and tumorigenesis in cells of the melanocyte lineage. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Figure 1

17 pages, 1740 KiB

Open AccessArticle

Abscopal Response in Metastatic Melanoma: Real-World Data of a Retrospective, Multicenter Study

by Luc Ollivier, Charles Orione, Paul Bore, Laurent Misery, Delphine Legoupil, Jean-Christophe Leclere, Anne Coste, Gilles Girault, Iona Sicard-Cras, Clemence Kacperek, Francois Lucia, Dinu Stefan, François Thillays, Emmanuel Rio, Paul Lesueur, Christian Berthou, Dominique Heymann, Stéphane Champiat, Stéphane Supiot, Loig Vaugier and William Kao Show full author list Hide full author list

Cancers 2022, 14(17), 4213; https://doi.org/10.3390/cancers14174213 - 30 Aug 2022

Cited by 3 | Viewed by 2109

Abstract

Objective: To evaluate the incidence of the abscopal response (AR) in patients with metastatic melanoma requiring palliative radiotherapy (RT). Patients and methods: Patients treated for metastatic melanoma between January 1998 and February 2020 in four oncology departments were screened. Patients with progression under [...] Read more.

Objective: To evaluate the incidence of the abscopal response (AR) in patients with metastatic melanoma requiring palliative radiotherapy (RT). Patients and methods: Patients treated for metastatic melanoma between January 1998 and February 2020 in four oncology departments were screened. Patients with progression under immune checkpoint inhibitors or without ongoing systemic treatment, and requiring palliative RT were considered. The AR was defined as an objective response according to RECIST and/or iRECIST for at least one non-irradiated metastasis at distance (≥10 cm) from the irradiated lesion. Primary endpoint was the rate of AR. Secondary endpoints were overall survival (OS), progression-free survival (PFS), local control (LC) of the irradiated lesion, and toxicity as assessed by CTCAE v5. Results: Over the period considered, 118 patients were included and analyzed. Fifteen patients (12.7%) had an AR. With a median follow-up of 7.7 months (range, 0.2–242.2), median OS and PFS after RT were significantly longer in patients with an AR compared to those without: 28 vs. 6.6 months (p < 0.01) and not reached vs. 3.2 months, respectively. No grade ≥2 toxicity was reported. Patients who developed an AR were more likely to be treated with immunotherapy (93.3% vs. 55.9%, p = 0.02). In multivariate analysis, they had a higher number of irradiated metastases treated concomitantly (HR = 16.9, p < 0.01) and a higher rate of mild infections during RT (HR = 403.5, p < 0.01). Conclusions: AR in metastatic melanoma seems to be highly prognostic of overall survival, although it is a rare phenomenon. It may be promoted by multiple concomitant treatments with RT and immunotherapy and by acute inflammatory events such as infection. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Figure 1

9 pages, 1201 KiB

Open AccessCommunication

YK-4-279 Attenuates Progression of Pre-Existing Pigmented Lesions to Nodular Melanoma in a Mouse Model

by Lee Huang, Yougang Zhai, Cristian D. Fajardo and Deborah Lang

Cancers 2022, 14(1), 143; https://doi.org/10.3390/cancers14010143 - 29 Dec 2021

Cited by 1 | Viewed by 1408

Abstract

More options are needed for the effective treatment of melanoma. In a previous study, we discovered the small molecule drug YK-4-279 almost completely inhibited tumor progression in the Braf^CA;Tyr-CreERT2;Pten^flox/flox transgenic mouse model. YK-4-279 had no effect on [...] Read more.

More options are needed for the effective treatment of melanoma. In a previous study, we discovered the small molecule drug YK-4-279 almost completely inhibited tumor progression in the Braf^CA;Tyr-CreERT2;Pten^flox/flox transgenic mouse model. YK-4-279 had no effect on tumor initiation but blocked progression of invasive melanoma. Our current study was designed as a treatment model, where YK-4-279 was administered during pigmented lesion formation. The study design included the use of three groups: (1) a control group that received only DMSO without a drug (MOCK), (2) mice following our prior studies with YK-4-279 administered at the time of tumor induction (YK-4-279), and (3) mice treated during tumor initiation (YK-4-279 delay). While the MOCK mice had progression of tumors, both YK-4-279 and YK-4-279 delay groups had a significant block or delay of progression. The majority of mice in the YK-4-279 groups had a block of progression, while the YK-4-279 delay group had either a partial block (60% in male mice or 29% in females) or a delay in disease progression in females (28 days in controls to 50 days in YK-4-279 delay group). Here, we demonstrate that YK-4-279 has a significant impact on blocking or delaying tumor progression in a pre-clinical treatment model of melanoma. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Figure 1

13 pages, 911 KiB

Open AccessArticle

Differences in Uveal Melanoma Age-Standardized Incidence Rates in Two Eastern States of Australia Are Driven by Differences in Rurality and Ultraviolet Radiation

by Melissa Chalada, Charmaine A. Ramlogan-Steel, Bijay P. Dhungel, Amanda Y. Goh, Samuel Gardiner, Christopher J. Layton and Jason C. Steel

Cancers 2021, 13(23), 5894; https://doi.org/10.3390/cancers13235894 - 23 Nov 2021

Cited by 3 | Viewed by 1866

Abstract

Uveal melanoma (UM) is the second-most-common melanoma in humans and has a high age-standardized incidence rate (ASR) in Australia. Regional patterns of UM ASRs in Australia are unknown. The aim of this study was to determine and compare UM ASRs in two geographically [...] Read more.

Uveal melanoma (UM) is the second-most-common melanoma in humans and has a high age-standardized incidence rate (ASR) in Australia. Regional patterns of UM ASRs in Australia are unknown. The aim of this study was to determine and compare UM ASRs in two geographically disparate eastern states, Queensland (QLD) and Victoria (VIC), by using cancer registry data that was obtained from 2001 to 2013. World-standardized UM ASRs and incidence-rate ratios (IRRs) were calculated. Higher UM ASR was also observed in anterior UM compared to posterior UM ASR. UM ASR remained unchanged from 2001 to 2013 in QLD but decreased in VIC. A south-to-north latitude trend in UM ASR along the east of Australia is weakly evident, and rural populations have higher UM ASRs than major city populations in both states. Differences in ultraviolent radiation (UVR) susceptibility, indigenous populations, social behaviours, chemical exposure, and socioeconomic status could all be contributing to differences in UM rates between QLD and VIC and between rural compared to major city areas. It is possible that a minority of cases in QLD and VIC might be prevented by sun-protective behaviours. This is important, because these findings suggest that QLD, which is already known to have one of the highest cutaneous melanoma (CM) ASRs in the world, also has one of the highest UM ASRs. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Figure 1

17 pages, 4305 KiB

Open AccessArticle

Fibroblasts Influence Metastatic Melanoma Cell Sensitivity to Combined BRAF and MEK Inhibition

by Delphine Morales, Pascale Vigneron, Ines Ferreira, Warda Hamitou, Mikael Magnano, Laxsika Mahenthiran, Catherine Lok and Muriel Vayssade

Cancers 2021, 13(19), 4761; https://doi.org/10.3390/cancers13194761 - 23 Sep 2021

Cited by 3 | Viewed by 1960

Abstract

The sensitivity of melanoma cells to targeted therapy compounds depends on the tumor microenvironment. Three-dimensional (3D) in vitro coculture systems better reflect the native structural architecture of tissues and are ideal for investigating cellular interactions modulating cell sensitivity to drugs. Metastatic melanoma (MM) [...] Read more.

The sensitivity of melanoma cells to targeted therapy compounds depends on the tumor microenvironment. Three-dimensional (3D) in vitro coculture systems better reflect the native structural architecture of tissues and are ideal for investigating cellular interactions modulating cell sensitivity to drugs. Metastatic melanoma (MM) cells (SK-MEL-28 BRAF V600E mutant and SK-MEL-2 BRAF wt) were cultured as a monolayer (2D) or cocultured on 3D dermal equivalents (with fibroblasts) and treated with a BRAFi (vemurafenib) combined with a MEK inhibitor (MEKi, cobimetinib). The drug combination efficiently inhibited 2D and 3D MM cell proliferation and survival regardless of their BRAF status. Two-dimensional and three-dimensional cancer-associated fibroblasts (CAFs), isolated from a cutaneous MM biopsy, were also sensitive to the targeted therapy. Conditioned media obtained from healthy dermal fibroblasts or CAFs modulated the MM cell’s response differently to the treatment: while supernatants from healthy fibroblasts potentialized the efficiency of drugs on MM, those from CAFs tended to increase cell survival. Our data indicate that the secretory profiles of fibroblasts influence MM sensitivity to the combined vemurafenib and cobimetinib treatment and highlight the need for 3D in vitro cocultures representing the complex crosstalk between melanoma and CAFs during preclinical studies of drugs. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Figure 1

14 pages, 2072 KiB

Open AccessArticle

CCL20/TNF/VEGFA Cytokine Secretory Phenotype of Tumor-Associated Macrophages Is a Negative Prognostic Factor in Cutaneous Melanoma

by Alba Gutiérrez-Seijo, Elena García-Martínez, Celia Barrio-Alonso, Miriam Pareja-Malagón, Alejandra Acosta-Ocampo, María Eugenia Fernández-Santos, Amaya Puig-Kröger, Verónica Parra-Blanco, Enrique Mercader, Iván Márquez-Rodas, José Antonio Avilés-Izquierdo, Rafael Samaniego and Paloma Sánchez-Mateos

Cancers 2021, 13(16), 3943; https://doi.org/10.3390/cancers13163943 - 05 Aug 2021

Cited by 9 | Viewed by 2344

Abstract

TAMs constitute a large fraction of infiltrating immune cells in melanoma tissues, but their significance for clinical outcomes remains unclear. We explored diverse TAM parameters in clinically relevant primary cutaneous melanoma samples, including density, location, size, and polarization marker expression; in addition, because [...] Read more.

TAMs constitute a large fraction of infiltrating immune cells in melanoma tissues, but their significance for clinical outcomes remains unclear. We explored diverse TAM parameters in clinically relevant primary cutaneous melanoma samples, including density, location, size, and polarization marker expression; in addition, because cytokine production is a hallmark of macrophages function, we measured CCL20, TNF, and VEGFA intracellular cytokines by single-cell multiparametric confocal microscopy. The Kaplan–Meier method was used to analyze correlation with melanoma-specific disease-free survival and overall survival. No significant correlations with clinical parameters were observed for TAM density, morphology, or location. Significantly, higher contents of the intracellular cytokines CCL20, TNF, and VEGFA were quantified in TAMs infiltrating metastasizing compared to non-metastasizing skin primary melanomas (p < 0.001). To mechanistically explore cytokine up-regulation, we performed in vitro studies with melanoma-conditioned macrophages, using RNA-seq to explore involved pathways and specific inhibitors. We show that p53 and NF-κB coregulate CCL20, TNF, and VEGFA in melanoma-conditioned macrophages. These results delineate a clinically relevant pro-oncogenic cytokine profile of TAMs with prognostic significance in primary melanomas and point to the combined therapeutic targeting of NF-kB/p53 pathways to control the deviation of TAMs in melanoma. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Figure 1

17 pages, 872 KiB

Open AccessArticle

Development of a Metastatic Uveal Melanoma Prognostic Score (MUMPS) for Use in Patients Receiving Immune Checkpoint Inhibitors

by Deirdre Kelly, April A. N. Rose, Thiago Pimentel Muniz, David Hogg, Marcus O. Butler, Samuel D. Saibil, Ian King, Zaid Saeed Kamil, Danny Ghazarian, Kendra Ross, Marco Iafolla, Daniel V. Araujo, John Waldron, Normand Laperriere, Hatem Krema and Anna Spreafico

Cancers 2021, 13(14), 3640; https://doi.org/10.3390/cancers13143640 - 20 Jul 2021

Cited by 5 | Viewed by 2843

Abstract

Metastatic uveal melanoma (mUM) is a rare disease. There are limited data on prognostic clinical factors for overall survival (OS) in patients with mUM treated with immune checkpoint inhibitors (ICI). Retrospective and non-randomized prospective studies have reported response rates of 0–17% for anti-PD1/L1 [...] Read more.

Metastatic uveal melanoma (mUM) is a rare disease. There are limited data on prognostic clinical factors for overall survival (OS) in patients with mUM treated with immune checkpoint inhibitors (ICI). Retrospective and non-randomized prospective studies have reported response rates of 0–17% for anti-PD1/L1 ± anti-CTLA4 ICI in mUM, indicating a potential benefit only in a subset of patients. This study evaluates the characteristics associated with ICI benefit in patients with mUM. We performed a single-center retrospective cohort study of patients with mUM who received anti-PD1/L1 ± anti-CTLA4 ICI between 2014–2019. Clinical and genomic characteristics were collected from a chart review. Treatment response and clinical progression were determined by physician assessment. Multivariable Cox regression models and Kaplan–Meier log-rank tests were used to assess differences in clinical progression-free survival (cPFS) and OS between groups and identify clinical variables associated with ICI outcomes. We identified 71 mUM patients who received 75 lines of ICI therapy. Of these, 54 received anti-PD1/L1 alone, and 21 received anti-PD1/L1 + anti-CTLA4. Patient characteristics were: 53% female, 48% were 65 or older, 72% received one or fewer lines of prior therapy. Within our cohort, 53% of patients had developed metastatic disease <2 years after their initial diagnosis. Bone metastases were present in 12% of patients. The median cPFS was 2.7 months, and the median OS was 10.0 months. In multivariable analyses for both cPFS and OS, the following variables were associated with a good prognosis: ≥2 years from the initial diagnosis to metastatic disease (n = 25), LDH < 1.5 × ULN (n = 45), and absence of bone metastases (n = 66). We developed a Metastatic Uveal Melanoma Prognostic Score (MUMPS). Patients were divided into 3 MUMPS groups based on the number of the above-mentioned prognostic variables: Poor prognosis (0–1), Intermediate prognosis (2) and Good prognosis (3). Good prognosis patients experienced longer cPFS (6.0 months) and OS (34.5 months) than patients with intermediate (2.3 months cPFS, 9.4 months OS) and poor prognosis disease (1.8 months cPFS, 3.9 months OS); p < 0.0001. We developed MUMPS—a prognostic score based on retrospective data that is comprised of 3 readily available clinical variables (time to metastatic diagnosis, presence of bone metastases, and LDH). This MUMPS score has a potential prognostic value. Further validation in independent datasets is warranted to determine the role of this MUMPS score in selecting ICI treatment management for mUM. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Figure 1

15 pages, 2747 KiB

Open AccessArticle

Knocking out the Vitamin D Receptor Enhances Malignancy and Decreases Responsiveness to Vitamin D3 Hydroxyderivatives in Human Melanoma Cells

by Ewa Podgorska, Tae-Kang Kim, Zorica Janjetovic, Krystyna Urbanska, Robert C. Tuckey, Sejong Bae and Andrzej T. Slominski

Cancers 2021, 13(13), 3111; https://doi.org/10.3390/cancers13133111 - 22 Jun 2021

Cited by 14 | Viewed by 2415

Abstract

Vitamin D3 is not only involved in calcium and phosphate metabolism in humans, but it can also affect proliferation and differentiation of normal and cancer cells, including melanoma. The mechanism of the anti-cancer action of vitamin D3 is not fully understood. The nuclear [...] Read more.

Vitamin D3 is not only involved in calcium and phosphate metabolism in humans, but it can also affect proliferation and differentiation of normal and cancer cells, including melanoma. The mechanism of the anti-cancer action of vitamin D3 is not fully understood. The nuclear vitamin D receptor (VDR) is crucial for the phenotypic effects of vitamin D hydroxyderivatives. VDR expression shows an inverse correlation with melanoma progression and poor outcome of the disease. In this study we knocked out the VDR in a human melanoma cell line using CRISPR methodology. This enhanced the proliferation of melanoma cells grown in monolayer culture, spheroids or colonies and their migration. Activated forms of vitamin D, including classical 1,25(OH)₂D3, 20(OH)D3 and 1,20(OH)₂D3, inhibited cell proliferation, migration rate and the ability to form colonies and spheroids in the wild-type melanoma cell line, while VDR KO cells showed a degree of resistance to their action. These results indicate that expression of VDR is important for the inhibition of melanoma growth induced by activated forms of vitamin D. In conclusion, based on our previous clinicopathological analyses and the current study, we suggest that the VDR can function as a melanoma tumor suppressor gene. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Figure 1

12 pages, 313 KiB

Open AccessArticle

One-Year Morbidity Following Videoscopic Inguinal Lymphadenectomy for Stage III Melanoma

by Marnix R. Jansen, Otis M. Vrielink, Marloes Faut, Eric A. Deckers, Lukas B. Been and Barbara L. van Leeuwen

Cancers 2021, 13(6), 1450; https://doi.org/10.3390/cancers13061450 - 22 Mar 2021

Cited by 3 | Viewed by 1916

Abstract

Purpose: We aimed to elucidate morbidity following videoscopic inguinal lymphadenectomy for stage III melanoma. Methods: Melanoma patients who underwent a videoscopic inguinal lymphadenectomy between November 2015 and May 2019 were included. The measured outcomes were lymphedema and quality of life. Patients were reviewed [...] Read more.

Purpose: We aimed to elucidate morbidity following videoscopic inguinal lymphadenectomy for stage III melanoma. Methods: Melanoma patients who underwent a videoscopic inguinal lymphadenectomy between November 2015 and May 2019 were included. The measured outcomes were lymphedema and quality of life. Patients were reviewed one day prior to surgery and postoperatively every 3 months for one year. Results: A total number of 34 patients were included for participation; 19 (55.9%) patients underwent a concomitant iliac lymphadenectomy. Lymphedema incidence was 40% at 3 months and 50% at 12 months after surgery. Mean interlimb volume difference increased steadily from 1.8% at baseline to 6.9% at 12 months (p = 0.041). Median Lymph-ICF-LL total score increased from 0.0 at baseline to 12.0 at 3 months, and declined to 8.5 at 12 months (p = 0.007). Twelve months after surgery, Lymph-ICF-LL scores were higher for females (p = 0.021) and patients that received adjuvant radiotherapy (p = 0.013). The Median Distress Thermometer and EORTC QLQ-C30 summary score recovered to baseline at 12 months postoperatively (p = 0.747 and p = 0.203, respectively). Conclusions: The onset of lymphedema is rapid and continues to increase up to one year after videoscopic inguinal lymphadenectomy. Quality of life recovers to the baseline value. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Graphical abstract

Review

Jump to: Editorial, Research

25 pages, 1363 KiB

Open AccessReview

Alcohol as a Non-UV Social-Environmental Risk Factor for Melanoma

by Takeshi Yamauchi, Sarah Shangraw, Zili Zhai, Dinoop Ravindran Menon, Nisha Batta, Robert P. Dellavalle and Mayumi Fujita

Cancers 2022, 14(20), 5010; https://doi.org/10.3390/cancers14205010 - 13 Oct 2022

Cited by 2 | Viewed by 1871

Abstract

Although cancer mortality has declined among the general population, the incidence of melanoma continues to rise. While identifying high-risk cohorts with genetic risk factors improves public health initiatives and clinical care management, recognizing modifiable risk factors such as social-environmental risk factors would also [...] Read more.

Although cancer mortality has declined among the general population, the incidence of melanoma continues to rise. While identifying high-risk cohorts with genetic risk factors improves public health initiatives and clinical care management, recognizing modifiable risk factors such as social-environmental risk factors would also affect the methods of patient outreach and education. One major modifiable social-environmental risk factor associated with melanoma is ultraviolet (UV) radiation. However, not all forms of melanoma are correlated with sun exposure or occur in sun-exposed areas. Additionally, UV exposure is rarely associated with tumor progression. Another social-environmental factor, pregnancy, does not explain the sharply increased incidence of melanoma. Recent studies have demonstrated that alcohol consumption is positively linked with an increased risk of cancers, including melanoma. This perspective review paper summarizes epidemiological data correlating melanoma incidence with alcohol consumption, describes the biochemical mechanisms of ethanol metabolism, and discusses how ethanol and ethanol metabolites contribute to human cancer, including melanoma. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Figure 1

15 pages, 355 KiB

Open AccessReview

Zebrafish Syndromic Albinism Models as Tools for Understanding and Treating Pigment Cell Disease in Humans

by Sam J. Neuffer and Cynthia D. Cooper

Cancers 2022, 14(7), 1752; https://doi.org/10.3390/cancers14071752 - 30 Mar 2022

Cited by 8 | Viewed by 2502

Abstract

Melanin is the pigment that protects DNA from ultraviolet (UV) damage by absorbing excess energy. Melanin is produced in a process called melanogenesis. When melanogenesis is altered, diseases such as albinism result. Albinism can result in an increased skin cancer risk. Conversely, black [...] Read more.

Melanin is the pigment that protects DNA from ultraviolet (UV) damage by absorbing excess energy. Melanin is produced in a process called melanogenesis. When melanogenesis is altered, diseases such as albinism result. Albinism can result in an increased skin cancer risk. Conversely, black pigment cell (melanocyte) development pathways can be misregulated, causing excessive melanocyte growth that leads to melanoma (cancer of melanocytes). Zebrafish is an emerging model organism used to study pigment disorders due to their high fecundity, visible melanin development in melanophores (melanocytes in mammals) from 24 h post-fertilization, and conserved melanogenesis pathways. Here, we reviewed the conserved developmental pathways in zebrafish melanophores and mammalian melanocytes. Additionally, we summarized the progress made in understanding pigment cell disease and evidence supporting the strong potential for using zebrafish to find novel treatment options for albinism. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

28 pages, 1969 KiB

Open AccessEditor’s ChoiceReview

NRF2 and Key Transcriptional Targets in Melanoma Redox Manipulation

by Evan L. Carpenter, Alyssa L. Becker and Arup K. Indra

Cancers 2022, 14(6), 1531; https://doi.org/10.3390/cancers14061531 - 16 Mar 2022

Cited by 17 | Viewed by 5132

Abstract

Melanocytes are dendritic, pigment-producing cells located in the skin and are responsible for its protection against the deleterious effects of solar ultraviolet radiation (UVR), which include DNA damage and elevated reactive oxygen species (ROS). They do so by synthesizing photoprotective melanin pigments and [...] Read more.

Melanocytes are dendritic, pigment-producing cells located in the skin and are responsible for its protection against the deleterious effects of solar ultraviolet radiation (UVR), which include DNA damage and elevated reactive oxygen species (ROS). They do so by synthesizing photoprotective melanin pigments and distributing them to adjacent skin cells (e.g., keratinocytes). However, melanocytes encounter a large burden of oxidative stress during this process, due to both exogenous and endogenous sources. Therefore, melanocytes employ numerous antioxidant defenses to protect themselves; these are largely regulated by the master stress response transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2). Key effector transcriptional targets of NRF2 include the components of the glutathione and thioredoxin antioxidant systems. Despite these defenses, melanocyte DNA often is subject to mutations that result in the dysregulation of the proliferative mitogen-activated protein kinase (MAPK) pathway and the cell cycle. Following tumor initiation, endogenous antioxidant systems are co-opted, a consequence of elevated oxidative stress caused by metabolic reprogramming, to establish an altered redox homeostasis. This altered redox homeostasis contributes to tumor progression and metastasis, while also complicating the application of exogenous antioxidant treatments. Further understanding of melanocyte redox homeostasis, in the presence or absence of disease, would contribute to the development of novel therapies to aid in the prevention and treatment of melanomas and other skin diseases Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Figure 1

15 pages, 1056 KiB

Open AccessEditor’s ChoiceReview

Urological Melanoma: A Comprehensive Review of a Rare Subclass of Mucosal Melanoma with Emphasis on Differential Diagnosis and Therapeutic Approaches

by Gerardo Cazzato, Anna Colagrande, Antonietta Cimmino, Concetta Caporusso, Pragnell Mary Victoria Candance, Senia Maria Rosaria Trabucco, Marcello Zingarelli, Alfonso Lorusso, Maricla Marrone, Alessandra Stellacci, Francesca Arezzo, Andrea Marzullo, Gabriella Serio, Angela Filoni, Domenico Bonamonte, Paolo Romita, Caterina Foti, Teresa Lettini, Vera Loizzi, Gennaro Cormio, Leonardo Resta, Roberta Rossi and Giuseppe Ingravallo Show full author list Hide full author list

Cancers 2021, 13(17), 4424; https://doi.org/10.3390/cancers13174424 - 02 Sep 2021

Cited by 9 | Viewed by 2990

Abstract

Melanoma is reported as the 19th most common cancer worldwide, with estimated age-standardized incidence rates of 2.8–3.1 per 100,000. Although the origin is most frequently cutaneous, mucosal melanoma has been described several times in literature, and despite its rarity (only 1% of all [...] Read more.

Melanoma is reported as the 19th most common cancer worldwide, with estimated age-standardized incidence rates of 2.8–3.1 per 100,000. Although the origin is most frequently cutaneous, mucosal melanoma has been described several times in literature, and despite its rarity (only 1% of all melanomas), increasing attention is being paid to this disease form. Within this subgroup, melanomas of the uropoetic apparatus are a rarity among rarities. Indeed, less than 50 cases of primary melanoma originating from the urinary bladder have been described, and even less originating from the kidney, renal pelvis and urethra. In this work, we present a detailed review of the literature related to this subclass of mucosal melanoma, delve into the biological landscape of this neoplasm and discuss current approaches, future perspectives and potential therapeutic approaches. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Figure 1

21 pages, 2471 KiB

Open AccessReview

Glutamatergic Signaling a Therapeutic Vulnerability in Melanoma

by Kevinn Eddy and Suzie Chen

Cancers 2021, 13(15), 3874; https://doi.org/10.3390/cancers13153874 - 31 Jul 2021

Cited by 9 | Viewed by 3445

Abstract

Like other cancers, melanomas are associated with the hyperactivation of two major cell signaling cascades, the MAPK and PI3K/AKT pathways. Both pathways are activated by numerous genes implicated in the development and progression of melanomas such as mutated BRAF, RAS, and [...] Read more.

Like other cancers, melanomas are associated with the hyperactivation of two major cell signaling cascades, the MAPK and PI3K/AKT pathways. Both pathways are activated by numerous genes implicated in the development and progression of melanomas such as mutated BRAF, RAS, and NF1. Our lab was the first to identify yet another driver of melanoma, Metabotropic Glutamate Receptor 1 (protein: mGluR1, mouse gene: Grm1, human gene: GRM1), upstream of the MAPK and PI3K/AKT pathways. Binding of glutamate, the natural ligand of mGluR1, activates MAPK and PI3K/AKT pathways and sets in motion the deregulated cellular responses in cell growth, cell survival, and cell metastasis. In this review, we will assess the proposed modes of action that mediate the oncogenic properties of mGluR1 in melanoma and possible application of anti-glutamatergic signaling modulator(s) as therapeutic strategy for the treatment of melanomas. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Figure 1

41 pages, 1628 KiB

Open AccessReview

Neuroendocrine Factors in Melanoma Pathogenesis

by Cristian Scheau, Carmen Draghici, Mihaela Adriana Ilie, Mihai Lupu, Iulia Solomon, Mircea Tampa, Simona Roxana Georgescu, Ana Caruntu, Carolina Constantin, Monica Neagu and Constantin Caruntu

Cancers 2021, 13(9), 2277; https://doi.org/10.3390/cancers13092277 - 10 May 2021

Cited by 12 | Viewed by 4744

Abstract

Melanoma is one of the most aggressive skin cancers with a sharp rise in incidence in the last decades, especially in young people. Recognized as a significant public health issue, melanoma is studied with increasing interest as new discoveries in molecular signaling and [...] Read more.

Melanoma is one of the most aggressive skin cancers with a sharp rise in incidence in the last decades, especially in young people. Recognized as a significant public health issue, melanoma is studied with increasing interest as new discoveries in molecular signaling and receptor modulation unlock innovative treatment options. Stress exposure is recognized as an important component in the immune-inflammatory interplay that can alter the progression of melanoma by regulating the release of neuroendocrine factors. Various neurotransmitters, such as catecholamines, glutamate, serotonin, or cannabinoids have also been assessed in experimental studies for their involvement in the biology of melanoma. Alpha-MSH and other neurohormones, as well as neuropeptides including substance P, CGRP, enkephalin, beta-endorphin, and even cellular and molecular agents (mast cells and nitric oxide, respectively), have all been implicated as potential factors in the development, growth, invasion, and dissemination of melanoma in a variety of in vitro and in vivo studies. In this review, we provide an overview of current evidence regarding the intricate effects of neuroendocrine factors in melanoma, including data reported in recent clinical trials, exploring the mechanisms involved, signaling pathways, and the recorded range of effects. Full article

(This article belongs to the Special Issue Study on the Complex Melanoma)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Study on the Complex Melanoma

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (17 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI