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Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 56602

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Dr. Cristina M. Failla

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Experimental Immunology Laboratory, IDI-IRCCS, Rome, Italy
Interests: endothelial cells in inflammatory processes and in cell-to-cell cross talks; immune responses to skin tumors; 3D alternative models of human skin
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Prof. Dr. Eleonora Candi

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Department of Experimental Medicine, Università degli Studi di Roma “Tor Vergata”, Rome, Italy
Interests: the role of the transcription factor p63; homolog of p53; in epithelium development and tumor formation; p63-dependent metabolism changes in normal epithelia and in pathological conditions
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Dr. Antonio Facchiano

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Guest Editor

Laboratory of Molecular Oncology, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Rome, Italy
Interests: melanoma markers; angiogenic factors; melanoma therapy and diagnosis; autophagy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The publication of the first edition of this Special Issue has shown us that there is great interest in the field of skin cancer, and that many questions are still open and require additional investigation. As you know, skin cancer is the most common type of cancer, and its incidence is constantly increasing. Skin cancer comprises various skin tumor types, such as basal and squamous cell carcinomas, melanoma, Merkel cell carcinoma, cutaneous lymphomas, and other rare diseases, which present very different etiologies, incidences, therapeutic opportunities, and outcomes. Fortunately, research in recent years has brought novel and more effective therapeutic options, while others are foreseen in the near future. Nevertheless, open questions remain: which are the pathological drivers of skin cancers? What is the role of the skin microenvironment? Is there a role for the skin microbiota? Are there predictive biomarkers for immunotherapies? Are there molecular differences between skin cancer in young people and in adults? Is there a genetic predisposition to skin cancer? Is there a link between some therapeutic agents and skin cancer?

This second edition of the Special Issue intends to further highlight possible answers to these and other questions in the field, underlining research and clinical gaps and proposing opportunities for future studies. We welcome contributions focusing on molecular researches as well as more clinically-oriented researches to this new edition.

Dr. Cristina M. Failla
Prof. Dr. Eleonora Candi
Dr. Antonio Facchiano
Guest Editors

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Keywords

squamous cell carcinoma
basal cell carcinoma
melanoma
cutaneous lymphomas
tumor microenvironment
genetics

Related Special Issue

Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches in International Journal of Molecular Sciences (17 articles)

Published Papers (9 papers)

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Research

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23 pages, 7089 KiB

Open AccessArticle

In Model, In Vitro and In Vivo Killing Efficacy of Antitumor Peptide RDP22 on MUG-Mel2, a Patient Derived Cell Line of an Aggressive Melanoma Metastasis

by Maximiliane Wußmann, Florian Kai Groeber-Becker, Sabrina Riedl, Dina Alihodzic, Daniel Padaric, Lisa Gerlitz, Alexander Stallinger, Bernadette Liegl-Atzwanger, Dagmar Zweytick and Beate Rinner

Biomedicines 2022, 10(11), 2961; https://doi.org/10.3390/biomedicines10112961 - 17 Nov 2022

Cited by 1 | Viewed by 1669

Abstract

The host defense derived peptide was assessed in different model systems with increasing complexity employing the highly aggressive NRAS mutated melanoma metastases cell line MUG-Mel2. Amongst others, fluorescence microscopy and spectroscopy, as well as cell death studies were applied for liposomal, 2D and 3D in vitro models including tumor spheroids without or within skin models and in vivo mouse xenografts. Summarized, MUG-Mel2 cells were shown to significantly expose the negatively charged lipid phosphatidylserine on their plasma membranes, showing they are successfully targeted by RDP22. The peptide was able to induce cell death in MUG-Mel2 2D and 3D cultures, where it was able to kill tumor cells even inside the core of tumor spheroids or inside a melanoma organotypic model. In vitro studies indicated cell death by apoptosis upon peptide treatment with an LC₅₀ of 8.5 µM and seven-fold specificity for the melanoma cell line MUG-Mel2 over normal dermal fibroblasts. In vivo studies in mice xenografts revealed effective tumor regression upon intratumoral peptide injection, indicated by the strong clearance of pigmented tumor cells and tremendous reduction in tumor size and proliferation, which was determined histologically. The peptide RDP22 has clearly shown high potential against the melanoma cell line MUG-Mel2 in vitro and in vivo. Full article

(This article belongs to the Special Issue Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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17 pages, 1954 KiB

Open AccessArticle

Reduced Interleukin-17-Expressing Cells in Cutaneous Melanoma

by Anna Tosi, Lavinia Nardinocchi, Maria Luigia Carbone, Lorena Capriotti, Elena Pagani, Simona Mastroeni, Cristina Fortes, Fernanda Scopelliti, Caterina Cattani, Francesca Passarelli, Antonio Rosato, Stefania D’Atri, Cristina Maria Failla and Andrea Cavani

Biomedicines 2021, 9(12), 1930; https://doi.org/10.3390/biomedicines9121930 - 16 Dec 2021

Cited by 4 | Viewed by 2314

Abstract

Characterization of tumor associated lymphocytes (TILs) in tumor lesions is important to obtain a clear definition of their prognostic value and address novel therapeutic opportunities. In this work, we examined the presence of T helper (Th)17 lymphocytes in cutaneous melanoma. We performed an immunohistochemical analysis of a small cohort of primary melanomas, retrospectively selected. Thereafter, we isolated TILs from seven freshly surgically removed melanomas and from three basal cell carcinomas (BCC), as a comparison with a non-melanoma skin cancer known to retain a high amount of Th17 cells. In both studies, we found that, differently from BCC, melanoma samples showed a lower percentage of Th17 lymphocytes. Additionally, TIL clones could not be induced to differentiate towards the Th17 phenotype in vitro. The presence or absence of Th17 cells did not correlate with any patient characteristics. We only observed a lower amount of Th17 cells in samples from woman donors. We found a tendency towards an association between expression by melanoma cells of placenta growth factor, angiogenic factors able to induce Th17 differentiation, and presence of Th17 lymphocytes. Taken together, our data indicate the necessity of a deeper analysis of Th17 lymphocytes in cutaneous melanoma before correlating them with prognosis or proposing Th17-cell based therapeutic approaches. Full article

(This article belongs to the Special Issue Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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25 pages, 3623 KiB

Open AccessArticle

Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel–Hyaluronan Bioconjugate: In Vitro Evaluation in Non-Melanoma Skin Cancer

by Barbara Bellei, Silvia Caputo, Emilia Migliano, Gianluca Lopez, Valeria Marcaccini, Carlo Cota and Mauro Picardo

Biomedicines 2021, 9(6), 597; https://doi.org/10.3390/biomedicines9060597 - 24 May 2021

Cited by 6 | Viewed by 2548

Abstract

Background: Cancer-associated fibroblasts (CAFs) facilitate many aspects of cancer development by providing a structural framework rich in bioactive compounds. There are emerging studies proposing a combination of conventional anti-cancer therapies directed against neoplastic cells to molecules targeting tumor microenvironments. Methods: The study evaluated the pharmacological properties of the anti-tumor agent paclitaxel conjugated to hyaluronic acid (HA) regarding non-melanoma skin cancer (NMSC) and the surrounding fibroblasts. This molecule, named Oncofid-P20 (Onco-P20), preferentially targets cells expressing high levels of CD44, the natural ligand of HA. Results: Consistent with paclitaxel’s mechanism of action involving interference with the breakdown of microtubules during cell division, highly sensitive carcinoma cells rapidly underwent apoptotic cell death. Interestingly, less sensitive cells, such as dermal fibroblasts, resisted the Onco-P20 treatment and experienced a prolonged growth arrest characterized by morphological change and significant modification of the gene expression profile. Onco-P20-treated fibroblasts exhibited reduced growth factor production, downmodulation of the Wnt signaling pathway, and the acquisition of a marked pro-inflammatory profile. Independently of direct exposure to taxol, in the presence of Onco-P20-treated fibroblasts or in their conditioned medium, carcinoma cells had a reduced proliferation rate. Similar to NHF, fibroblasts isolated from skin cancer lesions or from adjacent tissue acquired anti-neoplastic activity under Onco-P20 treatment. Conclusion: Collectively, our data demonstrate that Onco-P20, exerting both a direct and an NHF-mediated indirect effect on carcinoma cells, is a candidate for an innovative therapy alternative to surgery for the treatment of NMSC. Full article

(This article belongs to the Special Issue Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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19 pages, 3120 KiB

Open AccessArticle

Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals

by Claudio Tabolacci, Martina Cordella, Sabrina Mariotti, Stefania Rossi, Cinzia Senatore, Carla Lintas, Lauretta Levati, Daniela D’Arcangelo, Antonio Facchiano, Stefania D’Atri, Roberto Nisini and Francesco Facchiano

Biomedicines 2021, 9(1), 79; https://doi.org/10.3390/biomedicines9010079 - 15 Jan 2021

Cited by 11 | Viewed by 3165

Abstract

The therapeutic success of BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) in BRAF-mutant melanoma is limited by the emergence of drug resistance, and several lines of evidence suggest that changes in the tumor microenvironment can play a pivotal role in acquired resistance. The present study focused on secretome profiling of melanoma cells sensitive or resistant to the BRAFi vemurafenib. Proteomic and cytokine/chemokine secretion analyses were performed in order to better understand the interplay between vemurafenib-resistant melanoma cells and the tumor microenvironment. We found that vemurafenib-resistant melanoma cells can influence dendritic cell (DC) maturation by modulating their activation and cytokine production. In particular, human DCs exposed to conditioned medium (CM) from vemurafenib-resistant melanoma cells produced higher levels of pro-inflammatory cytokines—that potentially facilitate melanoma growth—than DCs exposed to CM derived from parental drug-sensitive cells. Bioinformatic analysis performed on proteins identified by mass spectrometry in the culture medium from vemurafenib-sensitive and vemurafenib-resistant melanoma cells suggests a possible involvement of the proteasome pathway. Moreover, our data confirm that BRAFi-resistant cells display a more aggressive phenotype compared to parental ones, with a significantly increased production of interferon-γ, interleukin-8, vascular-endothelial growth factor, CD147/basigin, and metalloproteinase 2 (MMP-2). Plasma levels of CD147/basigin and MMP-2 were also measured before the start of therapy and at disease progression in a small group of melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib. A significant increment in CD147/basigin and MMP-2 was observed in all patients at the time of treatment failure, strengthening the hypothesis that CD147/basigin might play a role in BRAFi resistance. Full article

(This article belongs to the Special Issue Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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19 pages, 1637 KiB

Open AccessArticle

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

by Lenka Stolarova, Sandra Jelinkova, Radka Storchova, Eva Machackova, Petra Zemankova, Michal Vocka, Ondrej Kodet, Jan Kral, Marta Cerna, Zuzana Volkova, Marketa Janatova, Jana Soukupova, Viktor Stranecky, Pavel Dundr, Lenka Foretova, Libor Macurek, Petra Kleiblova and Zdenek Kleibl

Biomedicines 2020, 8(10), 404; https://doi.org/10.3390/biomedicines8100404 - 09 Oct 2020

Cited by 10 | Viewed by 4132

Abstract

Cutaneous melanoma is the deadliest skin malignity with a rising prevalence worldwide. Patients carrying germline mutations in melanoma-susceptibility genes face an increased risk of melanoma and other cancers. To assess the spectrum of germline variants, we analyzed 264 Czech melanoma patients indicated for testing due to early melanoma (at <25 years) or the presence of multiple primary melanoma/melanoma and other cancer in their personal and/or family history. All patients were analyzed by panel next-generation sequencing targeting 217 genes in four groups: high-to-moderate melanoma risk genes, low melanoma risk genes, cancer syndrome genes, and other genes with an uncertain melanoma risk. Population frequencies were assessed in 1479 population-matched controls. Selected POT1 and CHEK2 variants were characterized by functional assays. Mutations in clinically relevant genes were significantly more frequent in melanoma patients than in controls (31/264; 11.7% vs. 58/1479; 3.9%; p = 2.0 × 10⁻⁶). A total of 9 patients (3.4%) carried mutations in high-to-moderate melanoma risk genes (CDKN2A, POT1, ACD) and 22 (8.3%) patients in other cancer syndrome genes (NBN, BRCA1/2, CHEK2, ATM, WRN, RB1). Mutations in high-to-moderate melanoma risk genes (OR = 52.2; 95%CI 6.6–413.1; p = 3.2 × 10⁻⁷) and in other cancer syndrome genes (OR = 2.3; 95%CI 1.4–3.8; p = 0.003) were significantly associated with melanoma risk. We found an increased potential to carry these mutations (OR = 2.9; 95%CI 1.2–6.8) in patients with double primary melanoma, melanoma and other primary cancer, but not in patients with early age at onset. The analysis revealed affected genes in Czech melanoma patients and identified individuals who may benefit from genetic testing and future surveillance management of mutation carriers. Full article

(This article belongs to the Special Issue Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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Review

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23 pages, 3521 KiB

Open AccessReview

Merkel Cell Carcinoma

by Elena Dellambra, Maria Luigia Carbone, Francesca Ricci, Francesco Ricci, Francesca Romana Di Pietro, Gaia Moretta, Sofia Verkoskaia, Elisa Feudi, Cristina M. Failla, Damiano Abeni and Luca Fania

Biomedicines 2021, 9(7), 718; https://doi.org/10.3390/biomedicines9070718 - 23 Jun 2021

Cited by 11 | Viewed by 6322

Abstract

Merkel cell carcinoma (MCC) is a rare and extremely aggressive neuroendocrine carcinoma of the skin, with increasing incidence worldwide. This review intends to propose a comprehensive evaluation of MCC epidemiology, clinical features, pathogenetic mechanisms, diagnosis, and therapies. A section is dedicated to immunological aspects and another to the involvement of angiogenesis and angiogenic growth factors in MCC progression, proposing novel diagnostic and therapeutic approaches. Advanced MCC tumors have been treated with immune checkpoint inhibitors with effective results. Therefore, the state of art of this immunotherapy is also examined, reporting on the most recent clinical trials in the field. We conclude by underlining the achievements in the understanding of MCC pathology and indicating the present needs for effective diagnosis and therapeutic management of the disease. Full article

(This article belongs to the Special Issue Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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23 pages, 1318 KiB

Open AccessReview

Metabolic Interplay between the Immune System and Melanoma Cells: Therapeutic Implications

by Alice Indini, Francesco Grossi, Mario Mandalà, Daniela Taverna and Valentina Audrito

Biomedicines 2021, 9(6), 607; https://doi.org/10.3390/biomedicines9060607 - 26 May 2021

Cited by 12 | Viewed by 4094

Abstract

Malignant melanoma represents the most fatal skin cancer due to its aggressive biological behavior and high metastatic potential. Treatment strategies for advanced disease have dramatically changed over the last years due to the introduction of BRAF/MEK inhibitors and immunotherapy. However, many patients either display primary (i.e., innate) or eventually develop secondary (i.e., acquired) resistance to systemic treatments. Treatment resistance depends on multiple mechanisms driven by a set of rewiring processes, which involve cancer metabolism, epigenetic, gene expression, and interactions within the tumor microenvironment. Prognostic and predictive biomarkers are needed to guide patients’ selection and treatment decisions. Indeed, there are no recognized clinical or biological characteristics that identify which patients will benefit more from available treatments, but several biomarkers have been studied with promising preliminary results. In this review, we will summarize novel tumor metabolic pathways and tumor-host metabolic crosstalk mechanisms leading to melanoma progression and drug resistance, with an overview on their translational potential as novel therapeutic targets. Full article

(This article belongs to the Special Issue Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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33 pages, 4488 KiB

Open AccessEditor’s ChoiceReview

Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

by Luca Fania, Dario Didona, Francesca Romana Di Pietro, Sofia Verkhovskaia, Roberto Morese, Giovanni Paolino, Michele Donati, Francesca Ricci, Valeria Coco, Francesco Ricci, Eleonora Candi, Damiano Abeni and Elena Dellambra

Biomedicines 2021, 9(2), 171; https://doi.org/10.3390/biomedicines9020171 - 09 Feb 2021

Cited by 90 | Viewed by 14749

Abstract

Cutaneous squamous cell carcinoma (cSCC), a non-melanoma skin cancer, is a keratinocyte carcinoma representing one of the most common cancers with an increasing incidence. cSCC could be in situ (e.g., Bowen’s disease) or an invasive form. A significant cSCC risk factor is advanced age, together with cumulative sun exposure, fair skin, prolonged immunosuppression, and previous skin cancer diagnoses. Although most cSCCs can be treated by surgery, a fraction of them recur and metastasize, leading to death. cSCC could arise de novo or be the result of a progression of the actinic keratosis, an in situ carcinoma. The multistage process of cSCC development and progression is characterized by mutations in the genes involved in epidermal homeostasis and by several alterations, such as epigenetic modifications, viral infections, or microenvironmental changes. Thus, cSCC development is a gradual process with several histological- and pathological-defined stages. Dermoscopy and reflectance confocal microscopy enhanced the diagnostic accuracy of cSCC. Surgical excision is the first-line treatment for invasive cSCC. Moreover, radiotherapy may be considered as a primary treatment in patients not candidates for surgery. Extensive studies of cSCC pathogenic mechanisms identified several pharmaceutical targets and allowed the development of new systemic therapies, including immunotherapy with immune checkpoint inhibitors, such as Cemiplimab, and epidermal growth factor receptor inhibitors for metastatic and locally advanced cSCC. Furthermore, the implementation of prevention measures has been useful in patient management. Full article

(This article belongs to the Special Issue Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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38 pages, 7918 KiB

Open AccessEditor’s ChoiceReview

Basal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

by Luca Fania, Dario Didona, Roberto Morese, Irene Campana, Valeria Coco, Francesca Romana Di Pietro, Francesca Ricci, Sabatino Pallotta, Eleonora Candi, Damiano Abeni and Elena Dellambra

Biomedicines 2020, 8(11), 449; https://doi.org/10.3390/biomedicines8110449 - 23 Oct 2020

Cited by 65 | Viewed by 16405

Abstract

Basal cell carcinoma (BCC) is the most common human cancer worldwide, and is a subtype of nonmelanoma skin cancer, characterized by a constantly increasing incidence due to an aging population and widespread sun exposure. Although the mortality from BCC is negligible, this tumor can be associated with significant morbidity and cost. This review presents a literature overview of BCC from pathophysiology to novel therapeutic approaches. Several histopathological BCC subtypes with different prognostic values have been described. Dermoscopy and, more recently, reflectance confocal microscopy have largely improved BCC diagnosis. Although surgery is the first-line treatment for localized BCC, other nonsurgical local treatment options are available. BCC pathogenesis depends on the interaction between environmental and genetic characteristics of the patient. Specifically, an aberrant activation of Hedgehog signaling pathway is implicated in its pathogenesis. Notably, Hedgehog signaling inhibitors, such as vismodegib and sonidegib, are successfully used as targeted treatment for advanced or metastatic BCC. Furthermore, the implementation of prevention measures has demonstrated to be useful in the patient management. Full article

(This article belongs to the Special Issue Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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