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Molecular Aspects of Cutaneous Squamous Cell Carcinoma

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2019) | Viewed by 60173

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Prof. Dr. Carlo Pincelli

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Guest Editor

DermoLAB, Department of Surgical, Medical, Dental and Morphological Science, University of Modena and Reggio Emilia, 41124 Modena, Italy
Interests: autoimmune bullous diseases; keratinocyte biology; neurobiology of the skin
Special Issues, Collections and Topics in MDPI journals

Dr. Maria I. Morasso

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Guest Editor

Laboratory of Skin Biology, Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
Interests: epidermal differentiation; skin barrier formation; wound healing; epidermal homeostasis; skin inflammation; mouse models

Dr. Elisabetta Palazzo

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Assistant Editor

DermoLab, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy
Interests: skin cancer; squamous cell carcinoma; psoriasis; epidermal homeostasis; keratinocyte stem cells; epidermal differentiation; skin inflammation; mouse models; zebrafish models; in vitro skin 3D model; skin tumor spheroids; next-generation sequencing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cutaneous Squamous Cell Carcinoma (cSCC) represents the second most frequent skin cancer and has recently showed a rapid increase in incidence worldwide. cSCC results from a multistep carcinogenesis process, ranging from actinic keratosis to metastatic cSCC, and derives from molecular alterations of those pathways that regulate the balance between proliferation, differentiation and apoptosis of epidermal cells. If identified early, it can be surgically treated, but it might be disfiguring and costly. On the other hand, if left untreated, cSCC can rapidly grow and often metastasizes. Hence, the identification of molecular biomarkers or altered gene networks will give a key mean through which the development of more effective and accessible therapies could be possible.

Therefore, this Special Issue will accept research articles and reviews recapitulating all the molecular aspects of the biology and pathology of cSCC in both human and animal models, along with a description of significative biomarkers, including transcriptional regulators of gene expression, mutations linked to severe prognosis, drug resistance, or molecular target therapies.

Prof. Dr. Carlo Pincelli
Dr. Maria I. Morasso
Dr. Elisabetta Palazzo
Guest Editors

Manuscript Submission Information

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Keywords

Actinic keratosis
Squamous cell carcinoma
Epidermal differentiation
Hyperplasia
Transcription factors
Growth factor receptors
Animal models
Gene expression profiling
Chemotherapy
Molecular target therapy

Published Papers (11 papers)

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Editorial

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4 pages, 204 KiB

Open AccessEditorial

Molecular Approach to Cutaneous Squamous Cell Carcinoma: From Pathways to Therapy

by Elisabetta Palazzo, Maria I. Morasso and Carlo Pincelli

Int. J. Mol. Sci. 2020, 21(4), 1211; https://doi.org/10.3390/ijms21041211 - 12 Feb 2020

Cited by 4 | Viewed by 1970

Abstract

Cutaneous squamous cell carcinoma (cSCC) represents the second most frequent skin cancer, recently showing a rapid increase in incidence worldwide, with around >1 million cases/year in the United States and 2500 deaths [...] Full article

(This article belongs to the Special Issue Molecular Aspects of Cutaneous Squamous Cell Carcinoma)

Research

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11 pages, 6453 KiB

Open AccessCommunication

Do DLX3 and CD271 Protect Human Keratinocytes from Squamous Tumor Development?

by Elisabetta Palazzo, Alessandra Marconi, Carlo Pincelli and Maria I. Morasso

Int. J. Mol. Sci. 2019, 20(14), 3541; https://doi.org/10.3390/ijms20143541 - 19 Jul 2019

Cited by 6 | Viewed by 3328

Abstract

Well-regulated epidermal homeostasis depends on the function of different classes of factors, such as transcription regulators and receptors. Alterations in this homeostatic balance may lead to the development of cutaneous squamous tumorigenesis. The homeobox transcription factor DLX3 is determinant for a p53-dependent regulation of epidermal differentiation and modulates skin carcinogenesis. The maintenance of skin homeostasis also involves the action of neurotrophins (NTs) and their receptors, Trk and CD271. While Trk receptor overexpression is a hallmark of cancer, there are conflicting data on CD271 expression and function in cutaneous SCC (cSCC). Previous studies have reported NT receptors expression in head and neck SSC (HNSCC). We show that CD271 is expressed at low levels in primary cSCC cells and the number of CD271+ cells correlates with cell cohesion in SCC spheroids. In normal epidermis, CD271 is expressed in proliferative progenitor cells and DLX3 in terminally differentiated keratinocytes. Brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) increase DLX3 expression. In the absence of a functional BDNF receptor TrkB in keratinocytes, we hypothesize that the BDNF-dependent DLX3 response could be mediated via CD271. Altogether, our results support a putative CD271-DLX3 connection in keratinocytes, which might be crucial to preventing squamous skin cancer. Full article

(This article belongs to the Special Issue Molecular Aspects of Cutaneous Squamous Cell Carcinoma)

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26 pages, 3116 KiB

Open AccessArticle

A Unique Panel of Patient-Derived Cutaneous Squamous Cell Carcinoma Cell Lines Provides a Preclinical Pathway for Therapeutic Testing

by Sakinah Hassan, Karin J. Purdie, Jun Wang, Catherine A. Harwood, Charlotte M. Proby, Celine Pourreyron, Nikol Mladkova, Ai Nagano, Sandeep Dhayade, Dimitris Athineos, Matthew Caley, Viviana Mannella, Karen Blyth, Gareth J. Inman and Irene M. Leigh

Int. J. Mol. Sci. 2019, 20(14), 3428; https://doi.org/10.3390/ijms20143428 - 12 Jul 2019

Cited by 16 | Viewed by 4663

Abstract

Background: Cutaneous squamous cell carcinoma (cSCC) incidence continues to rise with increasing morbidity and mortality, with limited treatment options for advanced disease. Future improvements in targeted therapy will rely on advances in genomic/transcriptomic understanding and the use of model systems for basic research. We describe here the panel of 16 primary and metastatic cSCC cell lines developed and characterised over the past three decades in our laboratory in order to provide such a resource for future preclinical research and drug screening. Methods: Primary keratinocytes were isolated from cSCC tumours and metastases, and cell lines were established. These were characterised using short tandem repeat (STR) profiling and genotyped by whole exome sequencing. Multiple in vitro assays were performed to document their morphology, growth characteristics, migration and invasion characteristics, and in vivo xenograft growth. Results: STR profiles of the cSCC lines allow the confirmation of their unique identity. Phylogenetic trees derived from exome sequence analysis of the matched primary and metastatic lines provide insight into the genetic basis of disease progression. The results of in vivo and in vitro analyses allow researchers to select suitable cell lines for specific experimentation. Conclusions: There are few well-characterised cSCC lines available for widespread preclinical experimentation and drug screening. The described cSCC cell line panel provides a critical tool for in vitro and in vivo experimentation. Full article

(This article belongs to the Special Issue Molecular Aspects of Cutaneous Squamous Cell Carcinoma)

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15 pages, 1746 KiB

Open AccessArticle

Cell Type-Specific p38δ Targeting Reveals a Context-, Stage-, and Sex-Dependent Regulation of Skin Carcinogenesis

by Alexi Kiss, Aaron C. Koppel, Emily Murphy, Maxwell Sall, Meral Barlas, Grace Kissling and Tatiana Efimova

Int. J. Mol. Sci. 2019, 20(7), 1532; https://doi.org/10.3390/ijms20071532 - 27 Mar 2019

Cited by 9 | Viewed by 3625

Abstract

Activation and/or upregulated expression of p38δ are demonstrated in human skin malignancies including cutaneous squamous cell carcinoma, suggesting a role for p38δ in skin carcinogenesis. We previously reported that mice with germline deletion of the p38δ gene are significantly protected from chemical skin carcinogenesis. Here, we investigated the effects of cell-selective targeted ablation of p38δ in keratinocytes and in immune (myeloid) cells on skin tumor development in a two-stage 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) chemical mouse skin carcinogenesis model. Conditional keratinocyte-specific p38δ ablation (p38δ-cKO^∆K) did not influence the latency, incidence, or multiplicity of chemically-induced skin tumors, but led to increased tumor volume in females during the TPA promotion stage, and reduced malignant progression in males and females relative to their wild-type counterparts. In contrast, conditional myeloid cell-specific p38δ deletion (p38δ-cKO^∆M) inhibited DMBA/TPA-induced skin tumorigenesis in male but not female mice. Thus, tumor onset was delayed, and tumor incidence, multiplicity, and volume were reduced in p38δ-cKO^∆M males compared with control wild-type males. Moreover, the percentage of male mice with malignant tumors was decreased in the p38δ-cKO^∆M group relative to their wild-type counterparts. Collectively, these results reveal that cell-specific p38δ targeting modifies susceptibility to chemical skin carcinogenesis in a context-, stage-, and sex-specific manner. Full article

(This article belongs to the Special Issue Molecular Aspects of Cutaneous Squamous Cell Carcinoma)

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Review

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21 pages, 1112 KiB

Open AccessReview

Molecular Mechanisms of p63-Mediated Squamous Cancer Pathogenesis

by Michael A. Moses, Andrea L. George, Nozomi Sakakibara, Kanwal Mahmood, Roshini M. Ponnamperuma, Kathryn E. King and Wendy C. Weinberg

Int. J. Mol. Sci. 2019, 20(14), 3590; https://doi.org/10.3390/ijms20143590 - 23 Jul 2019

Cited by 57 | Viewed by 7947

Abstract

The p63 gene is a member of the p53/p63/p73 family of transcription factors and plays a critical role in development and homeostasis of squamous epithelium. p63 is transcribed as multiple isoforms; ΔNp63α, the predominant p63 isoform in stratified squamous epithelium, is localized to the basal cells and is overexpressed in squamous cell cancers of multiple organ sites, including skin, head and neck, and lung. Further, p63 is considered a stem cell marker, and within the epidermis, ΔNp63α directs lineage commitment. ΔNp63α has been implicated in numerous processes of skin biology that impact normal epidermal homeostasis and can contribute to squamous cancer pathogenesis by supporting proliferation and survival with roles in blocking terminal differentiation, apoptosis, and senescence, and influencing adhesion and migration. ΔNp63α overexpression may also influence the tissue microenvironment through remodeling of the extracellular matrix and vasculature, as well as by enhancing cytokine and chemokine secretion to recruit pro-inflammatory infiltrate. This review focuses on the role of ΔNp63α in normal epidermal biology and how dysregulation can contribute to cutaneous squamous cancer development, drawing from knowledge also gained by squamous cancers from other organ sites that share p63 overexpression as a defining feature. Full article

(This article belongs to the Special Issue Molecular Aspects of Cutaneous Squamous Cell Carcinoma)

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21 pages, 799 KiB

Open AccessReview

Complement System in Cutaneous Squamous Cell Carcinoma

by Pilvi Riihilä, Liisa Nissinen, Jaakko Knuutila, Pegah Rahmati Nezhad, Kristina Viiklepp and Veli-Matti Kähäri

Int. J. Mol. Sci. 2019, 20(14), 3550; https://doi.org/10.3390/ijms20143550 - 19 Jul 2019

Cited by 24 | Viewed by 13921

Abstract

Epidermal keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer with high mortality rates in the advanced stage. Chronic inflammation is a recognized risk factor for cSCC progression and the complement system, as a part of innate immunity, belongs to the microenvironment of tumors. The complement system is a double-edged sword in cancer, since complement activation is involved in anti-tumor cytotoxicity and immune responses, but it also promotes cancer progression directly and indirectly. Recently, the role of several complement components and inhibitors in the regulation of progression of cSCC has been shown. In this review, we will discuss the role of complement system components and inhibitors as biomarkers and potential new targets for therapeutic intervention in cSCC. Full article

(This article belongs to the Special Issue Molecular Aspects of Cutaneous Squamous Cell Carcinoma)

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11 pages, 629 KiB

Open AccessReview

Targeted Therapy Against the Cell of Origin in Cutaneous Squamous Cell Carcinoma

by Stephen J. Goldie, Ginevra Chincarini and Charbel Darido

Int. J. Mol. Sci. 2019, 20(9), 2201; https://doi.org/10.3390/ijms20092201 - 05 May 2019

Cited by 15 | Viewed by 4084

Abstract

Squamous cell carcinomas (SCC), including cutaneous SCCs, are by far the most frequent cancers in humans, accounting for 80% of all newly diagnosed malignancies worldwide. The old dogma that SCC develops exclusively from stem cells (SC) has now changed to include progenitors, transit-amplifying and differentiated short-lived cells. Accumulation of specific oncogenic mutations is required to induce SCC from each cell population. Whilst as fewer as one genetic hit is sufficient to induce SCC from a SC, multiple events are additionally required in more differentiated cells. Interestingly, the level of differentiation correlates with the number of transforming events required to induce a stem-like phenotype, a long-lived potential and a tumourigenic capacity in a progenitor, a transient amplifying or even in a terminally differentiated cell. Furthermore, it is well described that SCCs originating from different cells of origin differ not only in their squamous differentiation status but also in their malignant characteristics. This review summarises recent findings in cutaneous SCC and highlights transforming oncogenic events in specific cell populations. It underlines oncogenes that are restricted either to stem or differentiated cells, which could provide therapeutic target selectivity against heterogeneous SCC. This strategy may be applicable to SCC from different body locations, such as head and neck SCCs, which are currently still associated with poor survival outcomes. Full article

(This article belongs to the Special Issue Molecular Aspects of Cutaneous Squamous Cell Carcinoma)

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23 pages, 2555 KiB

Open AccessReview

MicroRNA Dysregulation in Cutaneous Squamous Cell Carcinoma

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

Int. J. Mol. Sci. 2019, 20(9), 2181; https://doi.org/10.3390/ijms20092181 - 02 May 2019

Cited by 72 | Viewed by 5912

Abstract

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and it can be locally invasive and metastatic to distant sites. MicroRNAs (miRNAs or miRs) are endogenous, small, non-coding RNAs of 19–25 nucleotides in length, that are involved in regulating gene expression at a post-transcriptional level. MicroRNAs have been implicated in diverse biological functions and diseases. In cancer, miRNAs can proceed either as oncogenic miRNAs (onco-miRs) or as tumor suppressor miRNAs (oncosuppressor-miRs), depending on the pathway in which they are involved. Dysregulation of miRNA expression has been shown in most of the tumors evaluated. MiRNA dysregulation is known to be involved in the development of cutaneous squamous cell carcinoma (CSCC). In this review, we focus on the recent evidence about the role of miRNAs in the development of CSCC and in the prognosis of this form of skin cancer. Full article

(This article belongs to the Special Issue Molecular Aspects of Cutaneous Squamous Cell Carcinoma)

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22 pages, 532 KiB

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The Role of the Immune System in Cutaneous Squamous Cell Carcinoma

by Matthew J. Bottomley, Jason Thomson, Catherine Harwood and Irene Leigh

Int. J. Mol. Sci. 2019, 20(8), 2009; https://doi.org/10.3390/ijms20082009 - 24 Apr 2019

Cited by 78 | Viewed by 5276

Abstract

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. In immunosuppressed populations it is a source of considerable morbidity and mortality due to its enhanced recurrence and metastatic potential. In common with many malignancies, leucocyte populations are both protective against cancer development and also play a role in ‘sculpting’ the nascent tumor, leading to loss of immunogenicity and tumor progression. UV radiation and chronic viral carriage may represent unique risk factors for cSCC development, and the immune system plays a key role in modulating the response to both. In this review, we discuss the lessons learned from animal and ex vivo human studies of the role of individual leucocyte subpopulations in the development of cutaneous SCC. We then discuss the insights into cSCC immunity gleaned from studies in humans, particularly in populations receiving pharmacological immunosuppression such as transplant recipients. Similar insights in other malignancies have led to exciting and novel immune therapies, which are beginning to emerge into the cSCC clinical arena. Full article

(This article belongs to the Special Issue Molecular Aspects of Cutaneous Squamous Cell Carcinoma)

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12 pages, 868 KiB

Open AccessReview

Telomeres and Telomerase in Cutaneous Squamous Cell Carcinoma

by Alessandra Ventura, Cristina Pellegrini, Ludovica Cardelli, Tea Rocco, Valeria Ciciarelli, Ketty Peris and Maria Concetta Fargnoli

Int. J. Mol. Sci. 2019, 20(6), 1333; https://doi.org/10.3390/ijms20061333 - 16 Mar 2019

Cited by 13 | Viewed by 3671

Abstract

The role of telomere biology and telomerase activation in skin cancers has been investigated in melanoma and basal cell carcinoma but limited evidence is available for cutaneous squamous cell carcinoma (cSCC). We will review the current knowledge on the role of telomere and telomerase pathway in cSCC pathogenesis. At the somatic level, both long and short telomere lengths have been described in cSCC. This telomere dichotomy is probably related to two different mechanisms of tumour initiation which determines two tumour subtypes. Telomere shortening is observed during the invasive progression from in situ forms of cSCC, such as Bowen’s disease (BD) and actinic keratosis (AK), to invasive cSCC. At the germline level, controversial results have been reported on the association between constitutive telomere length and risk of cSCC. Approximately 75–85% of cSCC tumours are characterized by a high level of telomerase activity. Telomerase activation has been also reported in AKs and BD and in sun-damaged skin, thus supporting the hypothesis that UV modulates telomerase activity in the skin. Activating TERT promoter mutations have been identified in 32–70% of cSCCs, with the majority showing the UV-signature. No significant correlation was observed between TERT promoter mutations and cSCC clinico-pathological features. However, TERT promoter mutations have been recently suggested to be independent predictors of an adverse outcome. The attention on telomere biology and telomerase activity in cSCC is increasing for the potential implications in the development of effective tools for prognostic assessment and of therapeutic strategies in patients with cutaneous cSCC. Full article

(This article belongs to the Special Issue Molecular Aspects of Cutaneous Squamous Cell Carcinoma)

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21 pages, 629 KiB

Open AccessReview

The Power of Fish Models to Elucidate Skin Cancer Pathogenesis and Impact the Discovery of New Therapeutic Opportunities

by Sreeja Sarasamma, Yu-Heng Lai, Sung-Tzu Liang, Kechun Liu and Chung-Der Hsiao

Int. J. Mol. Sci. 2018, 19(12), 3929; https://doi.org/10.3390/ijms19123929 - 07 Dec 2018

Cited by 13 | Viewed by 5128

Abstract

Animal models play important roles in investigating the pathobiology of cancer, identifying relevant pathways, and developing novel therapeutic tools. Despite rapid progress in the understanding of disease mechanisms and technological advancement in drug discovery, negative trial outcomes are the most frequent incidences during a Phase III trial. Skin cancer is a potential life-threatening disease in humans and might be medically futile when tumors metastasize. This explains the low success rate of melanoma therapy amongst other malignancies. In the past decades, a number of skin cancer models in fish that showed a parallel development to the disease in humans have provided important insights into the fundamental biology of skin cancer and future treatment methods. With the diversity and breadth of advanced molecular genetic tools available in fish biology, fish skin cancer models will continue to be refined and expanded to keep pace with the rapid development of skin cancer research. This review begins with a brief introduction of molecular characteristics of skin cancers, followed by an overview of teleost models that have been used in the last decades in melanoma research. Next, we will detail the importance of the zebrafish (Danio rerio) animal model and other emerging fish models including platyfish (Xiphophorus sp.), and medaka (Oryzias latipes) in future cutaneous malignancy studies. The last part of this review provides the recent development and genome editing applications of skin cancer models in zebrafish and the progress in small molecule screening. Full article

(This article belongs to the Special Issue Molecular Aspects of Cutaneous Squamous Cell Carcinoma)

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