International Journal of Molecular Sciences

Research

14 pages, 1641 KiB

Open AccessArticle

DNA Strand Break Properties of Protoporphyrin IX by X-ray Irradiation against Melanoma

by Takema Hasegawa, Junko Takahashi, Shinsuke Nagasawa, Motomichi Doi, Akihiro Moriyama and Hitoshi Iwahashi

Int. J. Mol. Sci. 2020, 21(7), 2302; https://doi.org/10.3390/ijms21072302 - 26 Mar 2020

Cited by 15 | Viewed by 3834

Abstract

Recent reports have suggested that 5-aminolevulinic acid (5-ALA), which is a precursor to protoporphyrin IX (PpIX), leads to selective accumulation of PpIX in tumor cells and acts as a radiation sensitizer in vitro and in vivo in mouse models of melanoma, glioma, and [...] Read more.

Recent reports have suggested that 5-aminolevulinic acid (5-ALA), which is a precursor to protoporphyrin IX (PpIX), leads to selective accumulation of PpIX in tumor cells and acts as a radiation sensitizer in vitro and in vivo in mouse models of melanoma, glioma, and colon cancer. In this study, we investigated the effect of PpIX under X-ray irradiation through ROS generation and DNA damage. ROS generation by the interaction between PpIX and X-ray was evaluated by two kinds of probes, 3′-(p-aminophenyl) fluorescein (APF) for hydroxyl radical (•OH) detection and dihydroethidium (DHE) for superoxide (O₂^•-). •OH showed an increase, regardless of the dissolved oxygen. Meanwhile, the increase in O₂^•- was proportional to the dissolved oxygen. Strand breaks (SBs) of DNA molecule were evaluated by gel electrophoresis, and the enhancement of SBs was observed by PpIX treatment. We also studied the effect of PpIX for DNA damage in cells by X-ray irradiation using a B16 melanoma culture. X-ray irradiation induced γH2AX, DNA double-strand breaks (DSBs) in the context of chromatin, and affected cell survival. Since PpIX can enhance ROS generation even in a hypoxic state and induce DNA damage, combined radiotherapy treatment with 5-ALA is expected to improve therapeutic efficacy for radioresistant tumors. Full article

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

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10 pages, 2738 KiB

Open AccessArticle

Humanization of Tumor Stroma by Tissue Engineering as a Tool to Improve Squamous Cell Carcinoma Xenograft

by Sara Guerrero-Aspizua, Andrea González-Masa, Claudio J. Conti, Marta García, Esteban Chacón-Solano, Fernando Larcher and Marcela del Río

Int. J. Mol. Sci. 2020, 21(6), 1951; https://doi.org/10.3390/ijms21061951 - 12 Mar 2020

Cited by 4 | Viewed by 3153

Abstract

The role of stroma is fundamental in the development and behavior of epithelial tumors. In this regard, limited growth of squamous cell carcinomas (SCC) or cell-lines derived from them has been achieved in immunodeficient mice. Moreover, lack of faithful recapitulation of the original [...] Read more.

The role of stroma is fundamental in the development and behavior of epithelial tumors. In this regard, limited growth of squamous cell carcinomas (SCC) or cell-lines derived from them has been achieved in immunodeficient mice. Moreover, lack of faithful recapitulation of the original human neoplasia complexity is often observed in xenografted tumors. Here, we used tissue engineering techniques to recreate a humanized tumor stroma for SCCs grafted in host mice, by combining CAF (cancer associated fibroblasts)-like cells with a biocompatible scaffold. The stroma was either co-injected with epithelial cell lines derived from aggressive SCC or implanted 15 days before the injection of the tumoral cells, to allow its vascularization and maturation. None of the mice injected with the cell lines without stroma were able to develop a SCC. In contrast, tumors were able to grow when SCC cells were injected into previously established humanized stroma. Histologically, all of the regenerated tumors were moderately differentiated SCC with a well-developed stroma, resembling that found in the original human neoplasm. Persistence of human stromal cells was also confirmed by immunohistochemistry. In summary, we provide a proof of concept that humanized tumor stroma, generated by tissue engineering, can facilitate the development of epithelial tumors in immunodeficient mice. Full article

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

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15 pages, 5993 KiB

Open AccessArticle

The β-Blocker Carvedilol Prevented Ultraviolet-Mediated Damage of Murine Epidermal Cells and 3D Human Reconstructed Skin

by Mengbing Chen, Sherry Liang, Ayaz Shahid, Bradley T. Andresen and Ying Huang

Int. J. Mol. Sci. 2020, 21(3), 798; https://doi.org/10.3390/ijms21030798 - 25 Jan 2020

Cited by 14 | Viewed by 3257

Abstract

The β-blocker carvedilol prevents ultraviolet (UV)-induced skin cancer, but the mechanism is unknown. Since carvedilol possesses antioxidant activity, this study investigated whether carvedilol prevents oxidative photodamage of skin, a precursor event in skin carcinogenesis. The effects of carvedilol, metoprolol (a β-blocker without antioxidant [...] Read more.

The β-blocker carvedilol prevents ultraviolet (UV)-induced skin cancer, but the mechanism is unknown. Since carvedilol possesses antioxidant activity, this study investigated whether carvedilol prevents oxidative photodamage of skin, a precursor event in skin carcinogenesis. The effects of carvedilol, metoprolol (a β-blocker without antioxidant property), and 4-hydroxycarbazole (4-OHC, a carvedilol synthesis intermediate and a free radical scavenger) were compared on UV- or H₂O₂-induced cell death and reactive oxygen species (ROS) production in murine epidermal JB6 P+ cells. Although carvedilol attenuated cell death, metoprolol and 4-OHC failed to show protective effects. As expected, increased cellular ROS induced by H₂O₂ or UV was abolished by carvedilol and 4-OHC, but not by metoprolol. Consistently, carvedilol attenuated the formation of UV-induced cyclobutane pyrimidine dimers (CPDs) and release of prostaglandin E₂ in JB6 P+ cells. Carvedilol’s activity was further confirmed in full thickness 3D human reconstituted skin, where carvedilol attenuated UV-mediated epidermal thickening, the number of Ki-67 and p53 positive cells as well as CPD formation. Based on pathway-specific Polymerase Chain Reaction (PCR) Array analysis, carvedilol treatment in many cases normalized UV-induced expression changes in DNA repair genes. Thus, carvedilol’s photoprotective activity is not attributed to β-blockade or direct ROS-scavenging capacity, but likely via DNA repair regulation. Full article

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

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13 pages, 778 KiB

Open AccessCommunication

Verification of 5-Aminolevurinic Radiodynamic Therapy Using a Murine Melanoma Brain Metastasis Model

by Junko Takahashi, Shinsuke Nagasawa, Mitsushi J. Ikemoto, Chikara Sato, Mari Sato and Hitoshi Iwahashi

Int. J. Mol. Sci. 2019, 20(20), 5155; https://doi.org/10.3390/ijms20205155 - 17 Oct 2019

Cited by 13 | Viewed by 3801

Abstract

Melanoma is a highly aggressive cancer with a propensity for brain metastases. These can be treated by radiotherapy, but the radiation-resistant nature of melanoma makes the prognosis for melanoma patients with brain metastases poor. Previously, we demonstrated that treatment of mice with subcutaneous [...] Read more.

Melanoma is a highly aggressive cancer with a propensity for brain metastases. These can be treated by radiotherapy, but the radiation-resistant nature of melanoma makes the prognosis for melanoma patients with brain metastases poor. Previously, we demonstrated that treatment of mice with subcutaneous melanoma with 5-aminolevurinic acid (5-ALA) and X-rays in combination, (“radiodynamic therapy (RDT)”), instead of with 5-ALA and laser beams (“photodynamic therapy”), improved tumor suppression in vivo. Here, using the B16-Luc melanoma brain metastasis model, we demonstrate that 5-ALA RDT effectively treats brain metastasis. We also studied how 5-ALA RDT damages cells in vitro using a B16 melanoma culture. Cell culture preincubated with 5-ALA alone increased intracellular photosensitizer protoporphyrin IX. On X-ray irradiation, the cells enhanced their ∙OH radical generation, which subsequently induced γH2AX, a marker of DNA double-strand breaks in their nuclei, but decreased mitochondrial membrane potential. After two days, the cell cycle was arrested. When 5-ALA RDT was applied to the brain melanoma metastasis model in vivo, suppression of tumor growth was indicated. Therapeutic efficacy in melanoma treatment has recently been improved by molecular targeted drugs and immune checkpoint inhibitors. Treatment with these drugs is now expected to be combined with 5-ALA RDT to further improve therapeutic efficacy. Full article

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

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Review

Jump to: Research, Other

24 pages, 5997 KiB

Open AccessReview

Non-Melanoma Skin Cancers: Biological and Clinical Features

by Mauro Cives, Francesco Mannavola, Lucia Lospalluti, Maria Chiara Sergi, Gerardo Cazzato, Elisabetta Filoni, Federica Cavallo, Giuseppe Giudice, Luigia Stefania Stucci, Camillo Porta and Marco Tucci

Int. J. Mol. Sci. 2020, 21(15), 5394; https://doi.org/10.3390/ijms21155394 - 29 Jul 2020

Cited by 105 | Viewed by 10676

Abstract

Non-melanoma skin cancers (NMSCs) include basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and Merkel cell carcinoma (MCC). These neoplasms are highly diverse in their clinical presentation, as well as in their biological evolution. While the deregulation of the Hedgehog pathway is commonly [...] Read more.

Non-melanoma skin cancers (NMSCs) include basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and Merkel cell carcinoma (MCC). These neoplasms are highly diverse in their clinical presentation, as well as in their biological evolution. While the deregulation of the Hedgehog pathway is commonly observed in BCC, SCC and MCC are characterized by a strikingly elevated mutational and neoantigen burden. As result of our improved understanding of the biology of non-melanoma skin cancers, innovative treatment options including inhibitors of the Hedgehog pathway and immunotherapeutic agents have been recently investigated against these malignancies, leading to their approval by regulatory authorities. Herein, we review the most relevant biological and clinical features of NMSC, focusing on innovative treatment approaches. Full article

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

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23 pages, 675 KiB

Open AccessReview

Cutaneous Squamous Cell Carcinoma: From Biology to Therapy

by Roberto Corchado-Cobos, Natalia García-Sancha, Rogelio González-Sarmiento, Jesús Pérez-Losada and Javier Cañueto

Int. J. Mol. Sci. 2020, 21(8), 2956; https://doi.org/10.3390/ijms21082956 - 22 Apr 2020

Cited by 133 | Viewed by 14764

Abstract

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and its incidence continues to rise. Although CSCC usually display a benign clinical behavior, it can be both locally invasive and metastatic. The signaling pathways involved in CSCC development have [...] Read more.

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and its incidence continues to rise. Although CSCC usually display a benign clinical behavior, it can be both locally invasive and metastatic. The signaling pathways involved in CSCC development have given rise to targetable molecules in recent decades. In addition, the high mutational burden and increased risk of CSCC in patients under immunosuppression were part of the rationale for developing the immunotherapy for CSCC that has changed the therapeutic landscape. This review focuses on the molecular basis of CSCC and the current biology-based approaches of targeted therapies and immune checkpoint inhibitors. Another purpose of this review is to explore the landscape of drugs that may induce or contribute to the development of CSCC. Beginning with the pathogenetic basis of these drug-induced CSCCs, we move on to consider potential therapeutic opportunities for overcoming this adverse effect. Full article

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

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10 pages, 976 KiB

Open AccessReview

The Role of Erythroid Differentiation Regulator 1 (ERDR1) in the Control of Proliferation and Photodynamic Therapy (PDT) Response

by Sunyoung Park, Kyung Eun Kim, Hyun Jeong Park and Daeho Cho

Int. J. Mol. Sci. 2020, 21(7), 2603; https://doi.org/10.3390/ijms21072603 - 9 Apr 2020

Cited by 4 | Viewed by 3718

Abstract

Erythroid differentiation regulator 1 (ERDR1) was newly identified as a secreted protein that plays an essential role in maintaining cell growth homeostasis. ERDR1 enhances apoptosis at high cell densities, leading to the inhibition of cell survival. Exogenous ERDR1 treatment decreases cancer cell proliferation [...] Read more.

Erythroid differentiation regulator 1 (ERDR1) was newly identified as a secreted protein that plays an essential role in maintaining cell growth homeostasis. ERDR1 enhances apoptosis at high cell densities, leading to the inhibition of cell survival. Exogenous ERDR1 treatment decreases cancer cell proliferation and tumor growth as a result of increased apoptosis via the regulation of apoptosis-related gene expression. Moreover, ERDR1 plays a pivotal role in skin diseases; ERDR1 expression in actinic keratosis (AK) is negatively correlated with the increase in apoptosis. Because of its high specificity and efficiency, photodynamic therapy (PDT) is a common therapy for patients with various skin diseases, including cancer. Many studies indicate that apoptosis is mainly induced by PDT treatment. As an apoptosis inducer, the recovery of the ERDR1 expression after PDT is correlated with good therapeutic outcomes. Here, we review recent findings that highlight the function of ERDR1 in the control of apoptosis. Thus, ERDR1 may have a role in the apoptosis regulation of target cells in the lesions, as the recovery of its expression after PDT is correlated with good therapeutic outcomes. Full article

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

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15 pages, 2268 KiB

Open AccessReview

Paraneoplastic Dermatoses: A Brief General Review and an Extensive Analysis of Paraneoplastic Pemphigus and Paraneoplastic Dermatomyositis

by Dario Didona, Luca Fania, Biagio Didona, Rüdiger Eming, Michael Hertl and Giovanni Di Zenzo

Int. J. Mol. Sci. 2020, 21(6), 2178; https://doi.org/10.3390/ijms21062178 - 21 Mar 2020

Cited by 45 | Viewed by 9727

Abstract

Skin manifestations of systemic disease and malignancy are extremely polymorphous. Clinicians should be familiarized with paraneoplastic dermatoses in order to perform an early diagnosis of the underlying neoplasm. Lack of familiarity with cutaneous clues of internal malignancy may delay diagnosis and treatment of [...] Read more.

Skin manifestations of systemic disease and malignancy are extremely polymorphous. Clinicians should be familiarized with paraneoplastic dermatoses in order to perform an early diagnosis of the underlying neoplasm. Lack of familiarity with cutaneous clues of internal malignancy may delay diagnosis and treatment of cancer. In this review, we described several paraneoplastic dermatoses and discussed extensively two paradigmatic ones, namely paraneoplastic pemphigus and paraneoplastic dermatomyositis. Full article

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

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14 pages, 734 KiB

Open AccessReview

The Role of Dermal Fibroblasts in Nevoid Basal Cell Carcinoma Syndrome Patients: An Overview

by Barbara Bellei, Silvia Caputo, Anna Carbone, Vitaliano Silipo, Federica Papaccio, Mauro Picardo and Laura Eibenschutz

Int. J. Mol. Sci. 2020, 21(3), 720; https://doi.org/10.3390/ijms21030720 - 22 Jan 2020

Cited by 6 | Viewed by 3715

Abstract

Nevoid basal cell carcinoma syndrome (NBCCS), also named Gorlin syndrome, is a rare multisystem genetic disorder characterized by marked predisposition to basal cell carcinomas (BCCs), childhood medulloblastomas, maxillary keratocysts, celebral calcifications, in addition to various skeletal and soft tissue developmental abnormalities. Mutations in [...] Read more.

Nevoid basal cell carcinoma syndrome (NBCCS), also named Gorlin syndrome, is a rare multisystem genetic disorder characterized by marked predisposition to basal cell carcinomas (BCCs), childhood medulloblastomas, maxillary keratocysts, celebral calcifications, in addition to various skeletal and soft tissue developmental abnormalities. Mutations in the tumor suppressor gene PATCHED1 (PTCH1) have been found to be associated in the majority of NBCCS cases. PATCH1 somatic mutations and loss of heterozygosity are also very frequent in sporadic BCCs. Unlike non-syndromic patients, NBCCS patients develop multiple BCCs in sun-protected skin area starting from early adulthood. Recent studies suggest that dermo/epidermal interaction could be implicated in BCC predisposition. According to this idea, NBCCS fibroblasts, sharing with keratinocytes the same PTCH1 germline mutation and consequent constitutive activation of the Hh pathway, display features of carcinoma-associated fibroblasts (CAF). This phenotypic traits include the overexpression of growth factors, specific microRNAs profile, modification of extracellular matrix and basement membrane composition, increased cytokines and pro-angiogenic factors secretion, and a complex alteration of the Wnt/β-catenin pathway. Here, we review studies about the involvement of dermal fibroblasts in BCC predisposition of Gorlin syndrome patients. Further, we matched the emerged NBCCS fibroblast profile to those of CAF to compare the impact of cell autonomous “pre-activated state” due to PTCH1 mutations to those of skin tumor stroma. Full article

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

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19 pages, 1497 KiB

Open AccessReview

Significance of 5-S-Cysteinyldopa as a Marker for Melanoma

by Kazumasa Wakamatsu, Satoshi Fukushima, Akane Minagawa, Toshikazu Omodaka, Tokimasa Hida, Naohito Hatta, Minoru Takata, Hisashi Uhara, Ryuhei Okuyama and Hironobu Ihn

Int. J. Mol. Sci. 2020, 21(2), 432; https://doi.org/10.3390/ijms21020432 - 9 Jan 2020

Cited by 16 | Viewed by 5001

Abstract

Melanoma is one of the most lethal and malignant cancers and its incidence is increasing worldwide, and Japan is not an exception. Although there are numerous therapeutic options for melanoma, the prognosis is still poor once it has metastasized. The main concern after [...] Read more.

Melanoma is one of the most lethal and malignant cancers and its incidence is increasing worldwide, and Japan is not an exception. Although there are numerous therapeutic options for melanoma, the prognosis is still poor once it has metastasized. The main concern after removal of a primary melanoma is whether it has metastasized, and early detection of metastatic melanoma would be effective in improving the prognosis of patients. Thus, it is very important to identify reliable methods to detect metastases as early as possible. Although many prognostic biomarkers (mainly for metastases) of melanoma have been reported, there are very few effective for an early diagnosis. Serum and urinary biomarkers for melanoma diagnosis have especially received great interest because of the relative ease of sample collection and handling. Several serum and urinary biomarkers appear to have significant potential both as prognostic indicators and as targets for future therapeutic methods, but still there are no efficient serum and urinary biomarkers for early detection, accurate diagnosis and prognosis, efficient monitoring of the disease and reliable prediction of survival and recurrence. Levels of 5-S-cysteinyldopa (5SCD) in the serum or urine as biomarkers of melanoma have been found to be significantly elevated earlier and to reflect melanoma progression better than physical examinations, laboratory tests and imaging techniques, such as scintigraphy and echography. With recent developments in the treatment of melanoma, studies reporting combinations of 5SCD levels and new applications for the treatment of melanoma are gradually increasing. This review summarizes the usefulness of 5SCD, the most widely used and well-known melanoma marker in the serum and urine, compares 5SCD and other useful markers, and finally its application to other fields. Full article

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

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16 pages, 961 KiB

Open AccessReview

Extracellular Vesicles and Epigenetic Modifications Are Hallmarks of Melanoma Progression

by Francesco Mannavola, Stella D’Oronzo, Mauro Cives, Luigia Stefania Stucci, Girolamo Ranieri, Franco Silvestris and Marco Tucci

Int. J. Mol. Sci. 2020, 21(1), 52; https://doi.org/10.3390/ijms21010052 - 20 Dec 2019

Cited by 41 | Viewed by 6082

Abstract

Cutaneous melanoma shows a high metastatic potential based on its ability to overcome the immune system’s control. The mechanisms activated for these functions vary extremely and are also represented by the production of a number of extracellular vesicles including exosomes. Other vesicles showing [...] Read more.

Cutaneous melanoma shows a high metastatic potential based on its ability to overcome the immune system’s control. The mechanisms activated for these functions vary extremely and are also represented by the production of a number of extracellular vesicles including exosomes. Other vesicles showing a potential role in the melanoma progression include oncosomes and melanosomes and the majority of them mediate tumor processes including angiogenesis, immune regulation, and modifications of the micro-environment. Moreover, a number of epigenetic modifications have been described in melanoma and abundant production of altered microRNAs (mi-RNAs), non-coding RNAs, histones, and abnormal DNA methylation have been associated with different phases of melanoma progression. In addition, exosomes, miRNAs, and other molecular factors have been used as potential biomarkers reflecting disease evolution while others have been suggested to be potential druggable molecules for therapeutic application. Full article

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

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17 pages, 1110 KiB

Open AccessReview

Role of Nicotinamide in Genomic Stability and Skin Cancer Chemoprevention

by Luca Fania, Cinzia Mazzanti, Elena Campione, Eleonora Candi, Damiano Abeni and Elena Dellambra

Int. J. Mol. Sci. 2019, 20(23), 5946; https://doi.org/10.3390/ijms20235946 - 26 Nov 2019

Cited by 57 | Viewed by 10709

Abstract

Nicotinamide (NAM) is an amide form of vitamin B3 and the precursor of nicotinamide adenine dinucleotide (NAD+), an essential co-enzyme of redox reactions for adenosine triphosphate (ATP) production and for other metabolic processes. As NAD+ status is critical in maintaining cellular energy, vitamin [...] Read more.

Nicotinamide (NAM) is an amide form of vitamin B3 and the precursor of nicotinamide adenine dinucleotide (NAD+), an essential co-enzyme of redox reactions for adenosine triphosphate (ATP) production and for other metabolic processes. As NAD+ status is critical in maintaining cellular energy, vitamin B3 deficiency mainly affects tissues that need high cellular energy causing pellagra and skin sun sensitivity. In animal models, NAD+ deficiency leads to UV sensitivity of the skin, impairs DNA damage response, and increases genomic instability and cancer incidence. Furthermore, NAD+ depletion is associated with human skin aging and cancer. NAM prevents the UV-induced ATP depletion boosting cellular energy and enhances DNA repair activity in vitro and in vivo. Moreover, NAM reduces skin cancer incidence and prevents the immune-suppressive effects of UV in mice. Thus, NAM is involved in the maintenance of genomic stability and may have beneficial effects against skin aging changes and tumor development. Clinical studies showed that topical use of NAM reduces cutaneous aging. Furthermore, oral NAM administration reduces the level of UV-mediated immunosuppression and lowers the rate of non-melanoma skin cancers in high-risk patients. Therefore, NAM replenishment strategy may be a promising approach for skin cancer chemoprevention. Full article

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

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17 pages, 9571 KiB

Open AccessReview

p63 Is a Promising Marker in the Diagnosis of Unusual Skin Cancer

by Artem Smirnov, Lucia Anemona, Flavia Novelli, Cristina M. Piro, Margherita Annicchiarico-Petruzzelli, Gerry Melino and Eleonora Candi

Int. J. Mol. Sci. 2019, 20(22), 5781; https://doi.org/10.3390/ijms20225781 - 17 Nov 2019

Cited by 24 | Viewed by 8693

Abstract

Skin cancer is the most common type of cancer worldwide. Ozone depletion and climate changes might cause a further increase in the incidence rate in the future. Although the early detection of skin cancer enables it to be treated successfully, some tumours can [...] Read more.

Skin cancer is the most common type of cancer worldwide. Ozone depletion and climate changes might cause a further increase in the incidence rate in the future. Although the early detection of skin cancer enables it to be treated successfully, some tumours can evolve and become more aggressive, especially in the case of melanoma. Therefore, good diagnostic and prognostic markers are needed to ensure correct detection and treatment. Transcription factor p63, a member of the p53 family of proteins, plays an essential role in the development of stratified epithelia such as skin. In this paper, we conduct a comprehensive review of p63 expression in different types of skin cancer and discuss its possible use in the diagnosis and prognosis of cutaneous tumours. Full article

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

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19 pages, 1624 KiB

Open AccessReview

Melanoma and Vitiligo: In Good Company

by Cristina Maria Failla, Maria Luigia Carbone, Cristina Fortes, Gianluca Pagnanelli and Stefania D’Atri

Int. J. Mol. Sci. 2019, 20(22), 5731; https://doi.org/10.3390/ijms20225731 - 15 Nov 2019

Cited by 40 | Viewed by 12043

Abstract

Cutaneous melanoma represents the most aggressive form of skin cancer, whereas vitiligo is an autoimmune disorder that leads to progressive destruction of skin melanocytes. However, vitiligo has been associated with cutaneous melanoma since the 1970s. Most of the antigens recognized by the immune [...] Read more.

Cutaneous melanoma represents the most aggressive form of skin cancer, whereas vitiligo is an autoimmune disorder that leads to progressive destruction of skin melanocytes. However, vitiligo has been associated with cutaneous melanoma since the 1970s. Most of the antigens recognized by the immune system are expressed by both melanoma cells and normal melanocytes, explaining why the autoimmune response against melanocytes that led to vitiligo could be also present in melanoma patients. Leukoderma has been also observed as a side effect of melanoma immunotherapy and has always been associated with a favorable prognosis. In this review, we discuss several characteristics of the immune system responses shared by melanoma and vitiligo patients, as well as the significance of occurrence of leukoderma during immunotherapy, with special attention to check-point inhibitors. Full article

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

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28 pages, 1428 KiB

Open AccessReview

Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: From Pathogenesis to Therapeutic Perspectives

by Angelo Giuseppe Condorelli, Elena Dellambra, Elena Logli, Giovanna Zambruno and Daniele Castiglia

Int. J. Mol. Sci. 2019, 20(22), 5707; https://doi.org/10.3390/ijms20225707 - 14 Nov 2019

Cited by 78 | Viewed by 10606

Abstract

Epidermolysis bullosa (EB) is a heterogeneous group of inherited skin disorders determined by mutations in genes encoding for structural components of the cutaneous basement membrane zone. Disease hallmarks are skin fragility and unremitting blistering. The most disabling EB (sub)types show defective wound healing, [...] Read more.

Epidermolysis bullosa (EB) is a heterogeneous group of inherited skin disorders determined by mutations in genes encoding for structural components of the cutaneous basement membrane zone. Disease hallmarks are skin fragility and unremitting blistering. The most disabling EB (sub)types show defective wound healing, fibrosis and inflammation at lesional skin. These features expose patients to serious disease complications, including the development of cutaneous squamous cell carcinomas (SCCs). Almost all subjects affected with the severe recessive dystrophic EB (RDEB) subtype suffer from early and extremely aggressive SCCs (RDEB-SCC), which represent the first cause of death in these patients. The genetic determinants of RDEB-SCC do not exhaustively explain its unique behavior as compared to low-risk, ultraviolet-induced SCCs in the general population. On the other hand, a growing body of evidence points to the key role of tumor microenvironment in initiation, progression and spreading of RDEB-SCC, as well as of other, less-investigated, EB-related SCCs (EB-SCCs). Here, we discuss the recent advances in understanding the complex series of molecular events (i.e., fibrotic, inflammatory, and immune processes) contributing to SCC development in EB patients, cross-compare tumor features in the different EB subtypes and report the most promising therapeutic approaches to counteract or delay EB-SCCs. Full article

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

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Other

Jump to: Research, Review

9 pages, 751 KiB

Open AccessCase Report

Multiple Sclerosis Treatment and Melanoma Development

by Maria Luigia Carbone, Pedro Miguel Lacal, Serena Messinese, Laura De Giglio, Carlo Pozzilli, Severino Persechino, Cinzia Mazzanti, Cristina Maria Failla and Gianluca Pagnanelli

Int. J. Mol. Sci. 2020, 21(8), 2950; https://doi.org/10.3390/ijms21082950 - 22 Apr 2020

Cited by 19 | Viewed by 3909

Abstract

Therapy of multiple sclerosis (MS) with disease-modifying agents such as natalizumab or fingolimod has been associated with the development of cutaneous melanoma. Here we briefly revise literature data and report of a case of a 48-year old woman who developed a melanoma and [...] Read more.

Therapy of multiple sclerosis (MS) with disease-modifying agents such as natalizumab or fingolimod has been associated with the development of cutaneous melanoma. Here we briefly revise literature data and report of a case of a 48-year old woman who developed a melanoma and several atypical naevi after sub sequential treatment with natalizumab (1 year) and fingolimod (7 years). By immunohistochemistry we observed the presence of T cells and leukocyte infiltration as well as of vascular endothelial growth factor (VEGF)-A expression in the patient melanoma biopsy. Then, we analyzed proliferation, migration and VEGF-A expression in three melanoma cell lines and found out that both natalizumab and fingolimod inhibited tumor cell proliferation but promoted or blocked cell migration depending on the cell line examined. VEGF-A secretion was augmented in one melanoma cell line only after fingolimod treatment. In conclusion, our in vitro data do not support the hypothesis of a direct action of natalizumab or fingolimod on melanoma progression but acting on the tumor microenvironment these treatments could indirectly favor melanoma evolution. Full article

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

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12 pages, 4426 KiB

Open AccessCase Report

Multiple Skin Squamous Cell Carcinomas in Junctional Epidermolysis Bullosa Due to Altered Laminin-332 Function

by Paola Fortugno, Angelo Giuseppe Condorelli, Elena Dellambra, Liliana Guerra, Francesca Cianfarani, Lavinia Tinaburri, Vittoria Proto, Naomi De Luca, Francesca Passarelli, Francesca Ricci, Giovanna Zambruno and Daniele Castiglia

Int. J. Mol. Sci. 2020, 21(4), 1426; https://doi.org/10.3390/ijms21041426 - 20 Feb 2020

Cited by 4 | Viewed by 3335

Abstract

Variably reduced expression of the basement membrane component laminin-332 (α3aβ3γ2) causes junctional epidermolysis bullosa generalized intermediate (JEB-GI), a skin fragility disorder with an increased susceptibility to squamous cell carcinoma (SCC) development in adulthood. Laminin-332 is highly expressed in several types of epithelial tumors [...] Read more.

Variably reduced expression of the basement membrane component laminin-332 (α3aβ3γ2) causes junctional epidermolysis bullosa generalized intermediate (JEB-GI), a skin fragility disorder with an increased susceptibility to squamous cell carcinoma (SCC) development in adulthood. Laminin-332 is highly expressed in several types of epithelial tumors and is central to signaling pathways that promote SCC tumorigenesis. However, laminin-332 mutations and expression in individuals affected by JEB-GI and suffering from recurrent SCCs have been poorly characterized. We studied a JEB-GI patient who developed over a hundred primary cutaneous SCCs. Molecular analysis combined with gene expression studies in patient skin and primary keratinocytes revealed that the patient is a functional hemizygous for the p.Cys1171* mutant allele which is transcribed in a stable mRNA encoding for a β3 chain shortened of the last two C-terminal amino acids (Cys1171-Lys1172). The lack of the Cys1171 residue involved in the C-terminal disulphide bond to γ2 chain did not prevent assembly, secretion, and proteolytic processing of the heterotrimeric molecule. Immunohistochemistry of SCC specimens revealed accumulation of mutant laminin-332 at the epithelial-stromal interface of invasive front. We conclude that the C-terminal disulphide bond is a structural element crucial for laminin-332 adhesion function in-vivo. By saving laminin-332 amount, processing, and signaling role the p.Cys1171* mutation may allow intrinsic pro-tumorigenic properties of the protein to be conveyed, thus contributing to invasiveness and recurrence of SCCs in this patient. Full article

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

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