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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 20 December 2024 | Viewed by 15109

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Special Issue Editors

Dr. Enrica Flori

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Guest Editor

IRCCS Istituto Dermatologico San Gallicano, 00144 Rome, Italy
Interests: skin inflammatory response; cross-talk among epidermal and dermal cells in pigmentary disorders; the role of nuclear receptors in the protective response against UV; skin cancer

Dr. Vittoria Maresca

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Guest Editor

IRCCS Istituto Dermatologico San Gallicano, 00144 Rome, Italy
Interests: melanocytes; melanoma cells; alpha-MSH; MC1R; MC1R signal transduction pathways

Dr. Giorgia Cardinali

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Guest Editor

San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy
Interests: bioactive modulators of cutaneous homeostasis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Skin cancer includes various types of skin tumors, such as melanoma, basal cell and squamous cell carcinomas, cutaneous lymphomas, and other rare diseases, which have very different etiologies, incidences, therapeutic approaches, and outcomes. The incidence of skin cancers is steadily increasing, representing a significant public health concern. In recent years, significant efforts have been made to develop effective therapeutic options, although many questions remain open. We welcome research contributions focused on understanding the molecular pathways, biomarkers, oxidative stress, and skin microenvironment involved in the onset and progression of skin cancers. Exploring the mechanisms of etiopathogenesis may contribute to developing new and more effective therapeutic approaches for the prevention and treatment of skin cancer. Note that pre-clinical and clinical contributions with biomolecular approaches will also be considered.

Dr. Enrica Flori
Dr. Vittoria Maresca
Dr. Giorgia Cardinali
Guest Editors

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Keywords

melanoma
squamous cell carcinoma
basal cell carcinoma
tumor microenvironment
epithelial–mesenchymal transition (EMT) process
ultraviolet radiation
oxidative stress
bioactive modulators
signal transduction pathways

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Published Papers (9 papers)

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Research

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27 pages, 3602 KiB

Open AccessArticle

Ecto-NOX Disulfide-Thiol Exchanger 2 (ENOX2/tNOX) Is a Potential Prognostic Marker in Primary Malignant Melanoma and May Serve as a Therapeutic Target

by Matti Böcker, Eftychia Chatziioannou, Heike Niessner, Constanze Hirn, Christian Busch, Kristian Ikenberg, Hubert Kalbacher, Rupert Handgretinger and Tobias Sinnberg

Int. J. Mol. Sci. 2024, 25(21), 11853; https://doi.org/10.3390/ijms252111853 - 4 Nov 2024

Viewed by 698

Abstract

With an increasing incidence of malignant melanoma, new prognostic biomarkers for clinical decision making have become more important. In this study, we evaluated the role of ecto-NOX disulfide-thiol exchanger 2 (ENOX2/tNOX), a cancer- and growth-associated protein, in the prognosis and therapy of primary malignant melanoma. We conducted a tissue microarray analysis of immunohistochemical ENOX2 protein expression and The Cancer Genome Atlas (TCGA) ENOX2 RNA expression analysis, as well as viability assays and Western blots of melanoma cell lines treated with the ENOX2 inhibitor phenoxodiol (PXD) and BRAF inhibitor (BRAFi) vemurafenib. We discovered that high ENOX2 expression is associated with decreased overall (OS), disease-specific (DSS) and metastasis-free survival (MFS) in primary melanoma (PM) and a reduction in electronic tumor-infiltrating lymphocytes (eTILs). A gradual rise in ENOX2 expression was found with an increase in malignant potential from benign nevi (BNs) via PMs to melanoma metastases (MMs), as well as with an increasing tumor thickness and stage. These results highlight the important role of ENOX2 in cancer growth, progression and metastasis. The ENOX2 expression was not limited to malignant cell lines but could also be found in keratinocytes, fibroblasts and melanocytes. The viability of melanoma cell lines could be inhibited by PXD. A reduced induction of phospho-AKT under PXD could prevent the development of acquired BRAFi resistance. In conclusion, ENOX2 may serve as a potential prognostic marker and therapeutic target in malignant melanoma. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer)

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15 pages, 3448 KiB

Open AccessArticle

Isothiocyanates Potentiate Tazemetostat-Induced Apoptosis by Modulating the Expression of Apoptotic Genes, Members of Polycomb Repressive Complex 2, and Levels of Tri-Methylating Lysine 27 at Histone 3 in Human Malignant Melanoma Cells

by Ioannis Anestopoulos, Ioannis Paraskevaidis, Sotiris Kyriakou, Lambrini E. Giova, Dimitrios T. Trafalis, Sotiris Botaitis, Rodrigo Franco, Aglaia Pappa and Mihalis I. Panayiotidis

Int. J. Mol. Sci. 2024, 25(5), 2745; https://doi.org/10.3390/ijms25052745 - 27 Feb 2024

Viewed by 1708

Abstract

In this study, we utilized an in vitro model consisting of human malignant melanoma as well as non-tumorigenic immortalized keratinocyte cells with the aim of characterizing the therapeutic effectiveness of the clinical epigenetic drug Tazemetostat alone or in combination with various isothiocyanates. In doing so, we assessed markers of cell viability, apoptotic induction, and expression levels of key proteins capable of mediating the therapeutic response. Our data indicated, for the first time, that Tazemetostat caused a significant decrease in viability levels of malignant melanoma cells in a dose- and time-dependent manner via the induction of apoptosis, while non-malignant keratinocytes were more resistant. Moreover, combinatorial treatment protocols caused a further decrease in cell viability, together with higher apoptotic rates. In addition, a significant reduction in the Polycomb Repressive Complex 2 (PRC2) members [e.g., Enhancer of Zeste Homologue 2 (EZH2), Embryonic Ectoderm Development (EED), and suppressor of zeste 12 (SUZ12)] and tri-methylating lysine 27 at Histone 3 (H3K27me3) protein expression levels was observed, at least partially, under specific combinatorial exposure conditions. Reactivation of major apoptotic gene targets was determined at much higher levels in combinatorial treatment protocols than Tazemetostat alone, known to be involved in the induction of intrinsic and extrinsic apoptosis. Overall, we developed an optimized experimental therapeutic platform aiming to ensure the therapeutic effectiveness of Tazemetostat in malignant melanoma while at the same time minimizing toxicity against neighboring non-tumorigenic keratinocyte cells. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer)

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13 pages, 1494 KiB

Open AccessArticle

VEGFC Gene Expression Is Associated with Tumor Progression and Disease-Free Survival in Cutaneous Squamous Cell Carcinoma

by Omar García-Pérez, Leticia Melgar-Vilaplana, Inés Sifaoui, Aleksandra Śmietańska, Elizabeth Córdoba-Lanús and Ricardo Fernández-de-Misa

Int. J. Mol. Sci. 2024, 25(1), 379; https://doi.org/10.3390/ijms25010379 - 27 Dec 2023

Viewed by 1188

Abstract

Cutaneous squamous cell carcinoma (CSCC) is one of the most common cancers in the skin. CSCC belongs to the non-melanoma skin cancers, and its incidence is increasing every year around the world. The principal routes of tumor progression are related to angiogenesis and lymphangiogenesis. In this study, we assess the gene expression of the relevant biomarkers of both routes in 49 formalin-fixed paraffin-embedded (FFPE) CSCC samples in an attempt to determine a molecular profile that correlates with the tumor progression and disease-free survival (DFS). The results were enhanced by a posttranscriptional analysis using an immunofluorescence assay. Overexpression of the vascular endothelial growth factor C (VEGFC) gene was found in patients with tumor progression (p = 0.022) and in patients with perineural invasion (p = 0.030). An increased expression of protein VEGFC in samples with tumor progression supported these results (p = 0.050). In addition, DFS curves showed differences (p = 0.027) for tumors with absent-low VEGFC expression versus those with high levels of VEGFC expression. No significant influence on DFS was detected for the remaining analyzed genes. VEGFC expression was found to be a risk factor in the disease progression (HR = 2.675; 95% CI: 1.089–6.570; p = 0.032). Our main results suggest that VEGFC gene expression is closely related to tumor progression, DFS, and the presence of perineural invasion. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer)

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17 pages, 2751 KiB

Open AccessArticle

A Side-by-Side Comparison of Wildtype and Variant Melanocortin 1 Receptor Signaling with Emphasis on Protection against Oxidative Damage to DNA

by Sonia Cerdido, José Sánchez-Beltrán, Ana Lambertos, Marta Abrisqueta, Lidia Padilla, Cecilia Herraiz, Conchi Olivares, Celia Jiménez-Cervantes and José C. García-Borrón

Int. J. Mol. Sci. 2023, 24(18), 14381; https://doi.org/10.3390/ijms241814381 - 21 Sep 2023

Cited by 3 | Viewed by 1497

Abstract

Common variants of the MC1R gene coding the α-melanocyte stimulating hormone receptor are associated with light skin, poor tanning, blond or red hair, and increased melanoma risk, due to pigment-dependent and -independent effects. This complex phenotype is usually attributed to impaired activation of cAMP signaling. However, several MC1R variants show significant residual coupling to cAMP and efficiently activate mitogenic extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling. Yet, residual signaling and the key actions of wildtype and variant MC1R have never been assessed under strictly comparable conditions in melanocytic cells of identical genetic background. We devised a strategy based on CRISPR-Cas9 knockout of endogenous MC1R in a human melanoma cell line wildtype for BRAF, NRAS and NF1, followed by reconstitution with epitope-labeled MC1R constructs, and functional analysis of clones expressing comparable levels of wildtype, R151C or D294H MC1R. The proliferation rate, shape, adhesion, motility and sensitivity to oxidative DNA damage were compared. The R151C and D294H RHC variants displayed impaired cAMP signaling, intracellular stability similar to the wildtype, triggered ERK1/2 activation as effectively as the wildtype, and afforded partial protection against oxidative DNA damage, although less efficiently than the wildtype. Therefore, common melanoma-associated MC1R variants display biased signaling and significant genoprotective activity. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer)

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17 pages, 2763 KiB

Open AccessArticle

Role of Rho/MRTF in Aggressive Vemurafenib-Resistant Murine Melanomas and Immune Checkpoint Upregulation

by Bardees M. Foda and Richard R. Neubig

Int. J. Mol. Sci. 2023, 24(18), 13785; https://doi.org/10.3390/ijms241813785 - 7 Sep 2023

Cited by 1 | Viewed by 1601

Abstract

Cutaneous melanoma is the deadliest skin cancer. Most have Ras-MAPK pathway (BRAF^V600E or NRAS) mutations and highly effective targeted therapies exist; however, they and immune therapies are limited by resistance, in part driven by small GTPase (Rho and Rac) activation. To facilitate preclinical studies of combination therapies to provide durable responses, we describe the first mouse melanoma lines resistant to BRAF inhibitors. Treatment of mouse lines, YUMM1.7 and YUMMER, with vemurafenib (Vem), the BRAF^V600E-selective inhibitor, resulted in high-level resistance (IC₅₀ shifts 20–30-fold). Resistant cells showed enhanced activation of Rho and the downstream transcriptional coactivator, myocardin-related transcription factor (MRTF). Resistant cells exhibited increased stress fibers, nuclear translocation of MRTF-A, and an increased MRTF-A gene signature. Pharmacological inhibition of the Rho/MRTF pathway using CCG-257081 reduced viability of resistant lines and enhanced sensitivity to Vem. Remarkably, co-treatment of parental lines with Vem and CCG-257081 eliminated resistant colony development. Resistant cells grew more slowly in vitro, but they developed highly aggressive tumors with a shortened survival of tumor-bearing mice. Increased expression of immune checkpoint inhibitor proteins (ICIs) in resistant lines may contribute to aggressive in vivo behavior. Here, we introduce the first drug-resistant mouse melanoma models for assessing combinations of targeted and immune therapies. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer)

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Review

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16 pages, 4926 KiB

Open AccessReview

A Narrative Review of the Evolution of Diagnostic Techniques and Treatment Strategies for Acral Lentiginous Melanoma

by Myoung Eun Choi, Eun Ji Choi, Joon Min Jung, Woo Jin Lee, Yoon-Seo Jo and Chong Hyun Won

Int. J. Mol. Sci. 2024, 25(19), 10414; https://doi.org/10.3390/ijms251910414 - 27 Sep 2024

Viewed by 836

Abstract

Acral melanoma (AM) is a subtype of cutaneous melanoma located on the palms, soles, and nails. The pathogenesis of AM involves mechanical stimulation and characteristic tumor-promoting mutations, such as those in the KIT proto-oncogene. Dermoscopy is useful for diagnosing AM, which is characterized by parallel ridge patterns and irregular diffuse pigmentation. Although histopathological confirmation is the gold standard for diagnosing AM, lesions showing minimal histopathological changes should be considered early-stage AM if they clinically resemble it. Recently, immunohistochemical staining of preferentially expressed antigen in melanoma has been recognized as a useful method to distinguish benign from malignant melanocytic tumors. Research reveals that AM is associated with an immunosuppressive microenvironment characterized by increased numbers of M2 macrophages and regulatory T cells, alongside a decreased number of tumor-infiltrating lymphocytes. Mohs micrographic surgery or digit-sparing wide local excision has been explored to improve quality of life and replace wide local excision or proximal amputation. AM has a worse prognosis than other subtypes, even in the early stages, indicating its inherent aggressiveness. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer)

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21 pages, 845 KiB

Open AccessReview

The Comparative Oncology of Canine Malignant Melanoma in Targeted Therapy: A Systematic Review of In Vitro Experiments and Animal Model Reports

by Xiaohui He, Yu Gao, Yuqing Deng, Junying He, Ingo Nolte, Hugo Murua Escobar and Feng Yu

Int. J. Mol. Sci. 2024, 25(19), 10387; https://doi.org/10.3390/ijms251910387 - 26 Sep 2024

Viewed by 1123

Abstract

Canine malignant melanoma (CMM) is highly aggressive and mostly located in the oral cavity. CMM is the predominant type of canine oral malignancy and shows striking homologies with human mucosal melanoma. In comparative oncology, canine oral melanomas (COMs), as spontaneous tumor models, have the potential to acquire a unique value as a translational model of rare human melanoma subtypes. This review aims to provide a comprehensive summary of targeted therapies for canine malignant melanoma and to enrich the field of comparative oncology. Following the PRISMA guidelines, a comprehensive literature search was conducted across databases for studies from 1976 to April 2024. Studies were selected based on their relevance to targeted treatments. A total of 30 studies met the inclusion criteria. Based on the treatment approaches, the studies were further categorized into immunotherapies, small molecule signaling inhibitors, indirect kinase inhibitors, and other alternative strategies. Some treatments have been shown to result in stable disease or partial response, accounting for 29% (monoclonal antibody) and 76.5% (micro-RNA therapies) in clinical trials. Moreover, in vitro experiments of small molecule inhibitors, including cell signaling inhibitors and indirect kinase inhibitors, have shown the potential to be an effective treatment option for the development of therapeutic strategies in canine malignant melanoma. The observed response in in vitro experiments of CMM (particularly the oral and certain cutaneous subtypes) to drugs used in the treatment of human melanoma underlines the resemblance to human melanoma, therefore supporting the notion that CMM may be a valuable model for understanding rare human melanoma subtypes and exploring potential therapeutic avenues in preclinical trials. Finally, this literature review serves as a valuable resource for the development of therapeutic strategies for CMM and highlights the potential for translating these findings to human cancer treatment. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer)

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14 pages, 1883 KiB

Open AccessReview

Dysembryogenetic Pathogenesis of Basal Cell Carcinoma: The Evidence to Date

by Giovanni Nicoletti, Marco Saler, Umberto Moro and Angela Faga

Int. J. Mol. Sci. 2024, 25(15), 8452; https://doi.org/10.3390/ijms25158452 - 2 Aug 2024

Cited by 1 | Viewed by 803

Abstract

The Basal Cell Carcinoma (BCC) is a sort of unique tumour due to its combined peculiar histological features and clinical behaviour, such as the constant binary involvement of the epithelium and the stroma, the virtual absence of metastases and the predilection of specific anatomical sites for both onset and spread. A potential correlation between the onset of BCC and a dysembryogenetic process has long been hypothesised. A selective investigation of PubMed-indexed publications supporting this theory retrieved 64 selected articles published between 1901 and 2024. From our analysis of the literature review, five main research domains on the dysembryogenetic pathogenesis of BCC were identified: (1) The correlation between the topographic distribution of BCC and the macroscopic embryology, (2) the correlation between BCC and the microscopic embryology, (3) the genetic BCC, (4) the correlation between BCC and the hair follicle and (5) the correlation between BCC and the molecular embryology with a specific focus on the Hedgehog signalling pathway. A large amount of data from microscopic and molecular research consistently supports the hypothesis of a dysembryogenetic pathogenesis of BCC. Such evidence is promoting advances in the clinical management of this disease, with innovative targeted molecular therapies on an immune modulating basis being developed. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer)

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17 pages, 722 KiB

Open AccessReview

Cutaneous Melanoma: A Review of Multifactorial Pathogenesis, Immunohistochemistry, and Emerging Biomarkers for Early Detection and Management

by Laura Maria Gosman, Dana-Antonia Țăpoi and Mariana Costache

Int. J. Mol. Sci. 2023, 24(21), 15881; https://doi.org/10.3390/ijms242115881 - 1 Nov 2023

Cited by 21 | Viewed by 4509

Abstract

Cutaneous melanoma (CM) is an increasingly significant public health concern. Due to alarming mortality rates and escalating incidence, it is crucial to understand its etiology and identify emerging biomarkers for improved diagnosis and treatment strategies. This review aims to provide a comprehensive overview of the multifactorial etiology of CM, underscore the importance of early detection, discuss the molecular mechanisms behind melanoma development and progression, and shed light on the role of the potential biomarkers in diagnosis and treatment. The pathogenesis of CM involves a complex interplay of genetic predispositions and environmental exposures, ultraviolet radiation exposure being the predominant environmental risk factor. The emergence of new biomarkers, such as novel immunohistochemical markers, gene mutation analysis, microRNA, and exosome protein expressions, holds promise for improved early detection, and prognostic and personalized therapeutic strategies. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer)

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