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Cancers
Special Issues
Molecular Profiling, Detection, and Therapy of Squamous Cell Carcinomas
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Molecular Profiling, Detection, and Therapy of Squamous Cell Carcinomas

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (30 October 2023) | Viewed by 9236

Special Issue Editors

Dr. Josefina Pinon Hofbauer

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Guest Editor
EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
Interests: squamous cell carcinoma of the skin; tumor biology; tumor microenvironment; cancer (immune) therapy; contribution of microbiome to cancer formation
Dr. Christina Guttmann-Gruber

E-Mail Website
Guest Editor
EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
Interests: squamous cell carcinoma of the skin; tumor biology; cancer therapy; contribution of microbiome to cancer formation
Dr. Verena Wally

E-Mail Website
Guest Editor
EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
Interests: squamous cell carcinoma of the skin; tumor biology; tumor microenvironment; tumor detection and early diagnosis; tumor biomarkers

Special Issue Information

Dear Colleagues,

Squamous cell carcinoma (SCCs) constitutes one of the most prevalent solid cancers and is a major cause of deaths worldwide. SCCs comprise a wide range of tumors that originate in different organs and are classified according to their site of development, i.e., skin, head and neck, mouth, oesophagus, lung, cervix, prostate, bladder, etc. Genetic mutations, epigenetic modifications, altered gene expression and a supportive tumor microenvironment, featuring changes in epithelial, stromal, immune and endothelial components, drive the development and progression of the disease. Addressing various aspects of tumor heterogeneity is critical to the development of new molecular markers, as well as effective therapeutic approaches. Recent advances in various “omics” technologies now enable deeper insight into the complex cellular heterogeneity and signaling cascades underlying these tumors. For this Special Issue, we welcome original research articles and reviews that focus on (but not exclusively): profiling of SCCs that help unravel the complex molecular mechanisms underlying tumor development and progression; biomarkers that will improve detection, diagnosis and prediction of therapeutic success; and immune, cell or gene therapeutic approaches to combat SCCs. We also encourage the submission of scientific work that employs innovative technologies to investigate these aspects.

We look forward to your valued contributions to this special issue.

Dr. Josefina Pinon Hofbauer
Dr. Christina Guttmann-Gruber
Dr. Verena Wally
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • squamous cell carcinoma
  • tumor profiling
  • genetics
  • gene expression
  • biomarker
  • detection
  • therapy

Published Papers (5 papers)

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Research

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15 pages, 2111 KiB  
Article
Epidermolysis-Bullosa-Associated Squamous Cell Carcinomas Support an Immunosuppressive Tumor Microenvironment: Prospects for Immunotherapy
by David Rafei-Shamsabadi, Lena Scholten, Sisi Lu, Daniele Castiglia, Giovanna Zambruno, Andreas Volz, Andreas Arnold, Mina Saleva, Ludovic Martin, Kristin Technau-Hafsi, Frank Meiss, Dagmar von Bubnoff and Cristina Has
Cancers 2024, 16(2), 471; https://doi.org/10.3390/cancers16020471 - 22 Jan 2024
Cited by 1 | Viewed by 1265
Abstract
Cutaneous squamous cell carcinomas (SCCs) are a major complication of some subtypes of epidermolysis bullosa (EB), with high morbidity and mortality rates and unmet therapeutic needs. The high rate of endogenous mutations and the fibrotic stroma are considered to contribute to the pathogenesis. [...] Read more.
Cutaneous squamous cell carcinomas (SCCs) are a major complication of some subtypes of epidermolysis bullosa (EB), with high morbidity and mortality rates and unmet therapeutic needs. The high rate of endogenous mutations and the fibrotic stroma are considered to contribute to the pathogenesis. Patients with dystrophic EB (DEB) and Kindler EB (KEB) have the highest propensity for developing SCCs. Another patient group that develops high-risk SCCs is immunosuppressed (IS) patients, especially after organ transplantation. Herein, we interrogate whether immune checkpoint proteins and immunosuppressive enzymes are dysregulated in EB-associated SCCs as an immune resistance mechanism and compare the expression patterns with those in SCCs from IS patients, who frequently develop high-risk tumors and sporadic SCCs, and immunocompetent (IC) individuals. The expression of indoleamine 2,3-dioxygenase (IDO), programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), T cell immunoglobulin and mucin-domain-containing protein-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and inflammatory infiltrates (CD4, CD8, and CD68) was assessed via immunohistochemistry and semi-quantitative analysis in 30 DEB-SCCs, 22 KEB-SCCs, 106 IS-SCCs, and 100 sporadic IC-SCCs. DEB-SCCs expressed significantly higher levels of IDO and PD-L1 in tumor cells and PD-1 in the tumor microenvironment (TME) compared with SCCs from IC and IS individuals. The number of CD4-positive T cells per mm2 was significantly lower in DEB-SCCs compared with IC-SCCs. KEB-SCCs showed the lowest expression of the exhaustion markers TIM-3 and LAG-3 compared with all other groups. These findings identify IDO, PD-1, and PD-L1 to be increased in EB-SCCs and candidate targets for combinatory treatments, especially in DEB-SCCs. Full article
(This article belongs to the Special Issue Molecular Profiling, Detection, and Therapy of Squamous Cell Carcinomas)
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24 pages, 5697 KiB  
Article
Biomarker Discovery in Rare Malignancies: Development of a miRNA Signature for RDEB-cSCC
by Roland Zauner, Monika Wimmer, Sabine Atzmueller, Johannes Proell, Norbert Niklas, Michael Ablinger, Manuela Reisenberger, Thomas Lettner, Julia Illmer, Sonja Dorfer, Ulrich Koller, Christina Guttmann-Gruber, Josefina Piñón Hofbauer, Johann W. Bauer and Verena Wally
Cancers 2023, 15(13), 3286; https://doi.org/10.3390/cancers15133286 - 22 Jun 2023
Cited by 1 | Viewed by 1431
Abstract
Machine learning has been proven to be a powerful tool in the identification of diagnostic tumor biomarkers but is often impeded in rare cancers due to small patient numbers. In patients suffering from recessive dystrophic epidermolysis bullosa (RDEB), early-in-life development of particularly aggressive [...] Read more.
Machine learning has been proven to be a powerful tool in the identification of diagnostic tumor biomarkers but is often impeded in rare cancers due to small patient numbers. In patients suffering from recessive dystrophic epidermolysis bullosa (RDEB), early-in-life development of particularly aggressive cutaneous squamous-cell carcinomas (cSCCs) represents a major threat and timely detection is crucial to facilitate prompt tumor excision. As miRNAs have been shown to hold great potential as liquid biopsy markers, we characterized miRNA signatures derived from cultured primary cells specific for the potential detection of tumors in RDEB patients. To address the limitation in RDEB-sample accessibility, we analyzed the similarity of RDEB miRNA profiles with other tumor entities derived from the Cancer Genome Atlas (TCGA) repository. Due to the similarity in miRNA expression with RDEB-SCC, we used HN-SCC data to train a tumor prediction model. Three models with varying complexity using 33, 10 and 3 miRNAs were derived from the elastic net logistic regression model. The predictive performance of all three models was determined on an independent HN-SCC test dataset (AUC-ROC: 100%, 83% and 96%), as well as on cell-based RDEB miRNA-Seq data (AUC-ROC: 100%, 100% and 91%). In addition, the ability of the models to predict tumor samples based on RDEB exosomes (AUC-ROC: 100%, 93% and 100%) demonstrated the potential feasibility in a clinical setting. Our results support the feasibility of this approach to identify a diagnostic miRNA signature, by exploiting publicly available data and will lay the base for an improvement of early RDEB-SCC detection. Full article
(This article belongs to the Special Issue Molecular Profiling, Detection, and Therapy of Squamous Cell Carcinomas)
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13 pages, 2527 KiB  
Article
Identifying Key Regulators of Keratinization in Lung Squamous Cell Cancer Using Integrated TCGA Analysis
by Yusri Dwi Heryanto and Seiya Imoto
Cancers 2023, 15(7), 2066; https://doi.org/10.3390/cancers15072066 - 30 Mar 2023
Cited by 2 | Viewed by 2161
Abstract
Keratinization is one of lung squamous cell cancer’s (LUSC) hallmark histopathology features. Epithelial cells produce keratin to protect their integrity from external harmful substances. In addition to their roles as cell protectors, recent studies have shown that keratins have important roles in regulating [...] Read more.
Keratinization is one of lung squamous cell cancer’s (LUSC) hallmark histopathology features. Epithelial cells produce keratin to protect their integrity from external harmful substances. In addition to their roles as cell protectors, recent studies have shown that keratins have important roles in regulating either normal cell or tumor cell functions. The objective of this study is to identify the genes and microRNAs (miRNAs) that act as key regulators of the keratinization process in LUSC. To address this goal, we classified LUSC samples from GDC-TCGA databases based on their keratinization molecular signatures. Then, we performed differential analyses of genes, methylation, and miRNA expression between high keratinization and low keratinization samples. By reconstruction and analysis of the differentially expressed genes (DEGs) network, we found that TP63 and SOX2 were the hub genes that were highly connected to other genes and displayed significant correlations with several keratin genes. Methylation analysis showed that the P63, P73, and P53 DNA-binding motif sites were significantly enriched for differentially methylated probes. We identified SNAI2, GRHL3, TP63, ZNF750, and FOXE1 as the top transcription factors associated with these binding sites. Finally, we identified 12 miRNAs that influence the keratinization process by using miRNA–mRNA correlation analysis. Full article
(This article belongs to the Special Issue Molecular Profiling, Detection, and Therapy of Squamous Cell Carcinomas)
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Review

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29 pages, 3709 KiB  
Review
Chondroitin Sulfate Proteoglycan 4 as a Marker for Aggressive Squamous Cell Carcinoma
by Kathryn Chen, Joel Yong, Roland Zauner, Verena Wally, John Whitelock, Mila Sajinovic, Zlatko Kopecki, Kang Liang, Kieran Francis Scott and Albert Sleiman Mellick
Cancers 2022, 14(22), 5564; https://doi.org/10.3390/cancers14225564 - 13 Nov 2022
Cited by 3 | Viewed by 2646
Abstract
Chondroitin sulfate (CS) proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is currently under investigation as a marker of cancer malignancy, and as a potential target of anticancer drug treatment. CSPG4 acts as a driver of tumourigenesis by regulating turnover of the [...] Read more.
Chondroitin sulfate (CS) proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is currently under investigation as a marker of cancer malignancy, and as a potential target of anticancer drug treatment. CSPG4 acts as a driver of tumourigenesis by regulating turnover of the extracellular matrix (ECM) to promote tumour cell invasion, migration as well as inflammation and angiogenesis. While CSPG4 has been widely studied in certain malignancies, such as melanoma, evidence is emerging from global gene expression studies, which suggests a role for CSPG4 in squamous cell carcinoma (SCC). While relatively treatable, lack of widely agreed upon diagnostic markers for SCCs is problematic, especially for clinicians managing certain patients, including those who are aged or infirm, as well as those with underlying conditions such as epidermolysis bullosa (EB), for which a delayed diagnosis is likely lethal. In this review, we have discussed the structure of CSPG4, and quantitatively analysed CSPG4 expression in the tissues and pathologies where it has been identified to determine the usefulness of CSPG4 expression as a diagnostic marker and therapeutic target in management of malignant SCC. Full article
(This article belongs to the Special Issue Molecular Profiling, Detection, and Therapy of Squamous Cell Carcinomas)
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Other

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11 pages, 1076 KiB  
Systematic Review
Toll-like Receptor Agonists Are Unlikely to Provide Benefits in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis
by Sainiteesh Maddineni, Michelle Chen, Fred Baik, Vasu Divi, John B. Sunwoo and Andrey Finegersh
Cancers 2023, 15(17), 4386; https://doi.org/10.3390/cancers15174386 - 1 Sep 2023
Viewed by 1232
Abstract
Background: Recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) has poor survival rates. Immunotherapy is the standard of care for R/M HNSCC, but objective responses occur in a minority of patients. Toll-like receptor (TLR) agonists promote antitumor immune responses and [...] Read more.
Background: Recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) has poor survival rates. Immunotherapy is the standard of care for R/M HNSCC, but objective responses occur in a minority of patients. Toll-like receptor (TLR) agonists promote antitumor immune responses and have been explored in clinical trials. Methods: A search for clinical trials using TLR agonists in HNSCC was performed under PRISMA guidelines. Data on patient characteristics, safety, and efficacy were collected and analyzed. Results: Three phase 1b trials with 40 patients and three phase 2 trials with 352 patients studying TLR8 and TLR9 agonists in combination with other treatment regimens for HNSCC were included. In phase 2 trials, there was no significant change in the objective response rate (RR = 1.13, CI 0.80–1.60) or association with increased grade 3+ adverse events (RR = 0.91, CI 0.76–1.11) associated with TLR agonist use. Conclusion: TLR agonists do not appear to provide additional clinical benefits or increase adverse events in the treatment of HNSCC. Given these results across multiple clinical trials and drug regimens, it is unlikely that additional trials of TLR agonists will demonstrate clinical benefits in HNSCC. Full article
(This article belongs to the Special Issue Molecular Profiling, Detection, and Therapy of Squamous Cell Carcinomas)
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