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Cancers
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Head and Neck Cancers
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Head and Neck Cancers

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

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 73071

Special Issue Editors

Dr. Natalia Issaeva

E-Mail Website
Guest Editor
Department of Otolaryngology/Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Interests: head and neck cancer; HPV-associated malignancies; p53
Special Issues, Collections and Topics in MDPI journals
Dr. Travis P. Schrank

E-Mail Website
Guest Editor
Department of Otolaryngology/Head and Neck Surgery, University of North Carolina School of Medicine, Chapel Hill, NC, USA
Interests: cancer genomics, tumor heterogeneity, NRF2 signaling

Special Issue Information

Dear colleagues,

As a comprehensive term, “head and neck cancer” includes epithelial malignancies of the upper aerodigestive tract (nasal cavity, oral cavity, oropharynx, pharynx, hypopharynx, and larynx), cutaneous malignancies of the head and neck region, and malignant tumors arising from different cell types of the thyroid and salivary glands. The incidence of this group of diseases is slowly but consistently increasing. Because of the multifunctional anatomical intricacies of the head and neck, disease progression and therapy-related side effects often severely affect the patient’s appearance and self-image as well as their ability to breathe, speak, and swallow. Furthermore, many patients presenting at advanced stage face these challenges as well as an uncertain chance for cure, even with state-of-the-art treatment. These factors make head and neck cancers especially difficult for patients, as well as motivate us to push the field forward through basic and translational science.

Recent developments and improvements in high-throughput sequencing and proteomic technologies have produced an enormous amount of data and advanced our knowledge of the etiology, treatment resistance, and potential biomarkers of head and neck cancers. However, translation of these data into clinical progress has been, maybe as expected, more incremental. Areas in particular need of novel insights include the treatment of recurrent and metastatic disease as well as the personalization of treatment based on the molecular characteristics of individual tumors. For this Special Issue, we welcome basic translational and clinical research papers, professional opinions, and reviews in the broad field of head and neck cancers.

Dr. Natalia Issaeva
Dr. Travis P. Schrank
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.

Published Papers (19 papers)

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12 pages, 1944 KiB  
Article
Genotyping and Characterization of HPV Status, Hypoxia, and Radiosensitivity in 22 Head and Neck Cancer Cell Lines
by Eva-Leonne Göttgens, Marleen Ansems, William P. J. Leenders, Johan Bussink and Paul N. Span
Cancers 2021, 13(5), 1069; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13051069 - 03 Mar 2021
Cited by 5 | Viewed by 2961
Abstract
To study head and neck squamous cell carcinomas (HNSCC) in vitro, a large variety of HNSCC cell lines have been developed. Here, we characterize a panel of 22 HNSCC cell lines, thereby providing a tool for research into tumor-specific treatment options in HNSCC. [...] Read more.
To study head and neck squamous cell carcinomas (HNSCC) in vitro, a large variety of HNSCC cell lines have been developed. Here, we characterize a panel of 22 HNSCC cell lines, thereby providing a tool for research into tumor-specific treatment options in HNSCC. Both human papillomavirus (HPV) positive and HPV negative tumor cell lines were collected from commercial and collaborative sources. Short tandem repeat profiling was used to confirm or characterize the identity of the cell lines. Targeted sequencing was performed using a standard pathology single molecule Molecular Inversion Probe panel to detect mutations for 23 tumor suppressors and oncogenes. HPV status, p16 status, radiosensitivity data, and hypoxia data are summarized from all cell lines. We detected HPV transcripts in five cell lines, all of which overexpressed p16. One HPV negative cell line was also p16 positive. We detected mutations in KIT (SCCNij185), PIK3CA (SCCNij185), and CDKN2A (UT-SCC-5 and UT-SCC-38). TP53 mutations were the most frequent, occurring in 16/22 cell lines. HPV infection and TP53 mutations were almost mutually exclusive, with the exception of 93-VU-147T. The cell lines exhibited a wide range of sensitivities towards hypoxia and irradiation. Here, we provide a description of a set of frequently used HNSCC cell lines with diverse characteristics as found in HNSCC patients. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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9 pages, 1896 KiB  
Article
PD-L1 Testing and Squamous Cell Carcinoma of the Head and Neck: A Multicenter Study on the Diagnostic Reproducibility of Different Protocols
by Simona Crosta, Renzo Boldorini, Francesca Bono, Virginia Brambilla, Emanuele Dainese, Nicola Fusco, Andrea Gianatti, Vincenzo L’Imperio, Patrizia Morbini and Fabio Pagni
Cancers 2021, 13(2), 292; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13020292 - 14 Jan 2021
Cited by 38 | Viewed by 4728
Abstract
Immune checkpoint inhibitors for blocking the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis are now available for squamous cell carcinoma of the head and neck (HNSCC) in relapsing and/or metastatic settings. In this work, we compared the resulting combined positive [...] Read more.
Immune checkpoint inhibitors for blocking the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis are now available for squamous cell carcinoma of the head and neck (HNSCC) in relapsing and/or metastatic settings. In this work, we compared the resulting combined positive score (CPS) of PD-L1 using alternative methods adopted in routine clinical practice and determined the level of diagnostic agreement and inter-observer reliability in this setting. The study applied 5 different protocols on 40 tissue microarrays from HNSCC. The error rate of the individual protocols ranged from a minimum of 7% to a maximum of 21%, the sensitivity from 79% to 96%, and the specificity from 50% to 100%. In the intermediate group (1 ≤ CPS < 20), the majority of errors consisted of an underestimation of PD-L1 expression. In strong expressors, 5 out of 14 samples (36%) were correctly evaluated by all the protocols, but no protocol was able to correctly identify all the “strong expressors”. The overall inter-observer agreement in PD-L1 CPS reached 87%. The inter-observer reliability was moderate, with an ICC of 0.774 (95% CI (0.651; 0.871)). In conclusion, our study showed moderate interobserver reliability among different protocols. In order to improve the performances, adequate specific training to evaluate PD-L1 by CPS in the HNSCC setting should be coordinated. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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19 pages, 3829 KiB  
Article
Global Genome Demethylation Causes Transcription-Associated DNA Double Strand Breaks in HPV-Associated Head and Neck Cancer Cells
by Michael Hajek, Asel Biktasova, Andrew Sewell, Cyril Gary, Paul Cantalupo, Karen S. Anderson, Wendell G. Yarbrough and Natalia Issaeva
Cancers 2021, 13(1), 21; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13010021 - 23 Dec 2020
Cited by 8 | Viewed by 2533
Abstract
High levels of DNA methylation at CpG loci are associated with transcriptional repression of tumor suppressor genes and dysregulation of DNA repair genes. Human papilloma virus (HPV)-associated head and neck squamous cell carcinomas (HNSCC) have high levels of DNA methylation and methylation has [...] Read more.
High levels of DNA methylation at CpG loci are associated with transcriptional repression of tumor suppressor genes and dysregulation of DNA repair genes. Human papilloma virus (HPV)-associated head and neck squamous cell carcinomas (HNSCC) have high levels of DNA methylation and methylation has been associated with dampening of an innate immune response in virally infected cells. We have been exploring demethylation as a potential treatment in HPV+ HNSCC and recently reported results of a window clinical trial showing that HNSCCs are particularly sensitive to demethylating agent 5-azacytidine (5-aza). Mechanistically, sensitivity is partially due to downregulation of HPV genes expression and restoration of tumor suppressors p53 and Rb. Here, for the first time, we show that 5-azaC treatment of HPV+ HNSCC induces replication and transcription-associated DNA double strand breaks (DSBs) that occur preferentially at demethylated genomic DNA. Blocking replication or transcription prevented formation of DNA DSBs and reduced sensitivity of HPV-positive head and neck cancer cells to 5-azaC, demonstrating that both replication and active transcription are required for formation of DSBs associated with 5-azaC. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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18 pages, 3488 KiB  
Article
HNC0014, a Multi-Targeted Small-Molecule, Inhibits Head and Neck Squamous Cell Carcinoma by Suppressing c-Met/STAT3/CD44/PD-L1 Oncoimmune Signature and Eliciting Antitumor Immune Responses
by Jih-Chin Lee, Alexander T. H. Wu, Jia-Hong Chen, Wen-Yen Huang, Bashir Lawal, Ntlotlang Mokgautsi, Hsu-Shan Huang and Ching-Liang Ho
Cancers 2020, 12(12), 3759; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123759 - 14 Dec 2020
Cited by 25 | Viewed by 3375
Abstract
Despite advancements in diagnostic and standard treatment modalities, including surgery, radiotherapy, and chemotherapy, overall survival rates of advanced-stage head and neck squamous cell carcinoma (HNSCC) patients have remained stagnant for over three decades. Failure of these treatment modalities, coupled with post-therapy complications, underscores [...] Read more.
Despite advancements in diagnostic and standard treatment modalities, including surgery, radiotherapy, and chemotherapy, overall survival rates of advanced-stage head and neck squamous cell carcinoma (HNSCC) patients have remained stagnant for over three decades. Failure of these treatment modalities, coupled with post-therapy complications, underscores the need for alternative interventions and an in-depth understanding of the complex signaling networks involved in developing treatment resistance. Using bioinformatics tools, we identified an increased expression of c-Met, STAT3, and CD44 corresponding to a poor prognosis and malignant phenotype of HNSCC. Subsequently, we showed that tumorsphere-derived exosomes promoted cisplatin (CDDP) resistance and colony and tumorsphere formation in parental HNSCC cells, accompanied by an increased level of oncogenic/immune evasive markers, namely, c-Met, STAT3, CD44, and PD-L1. We then evaluated the therapeutic potential of a new small molecule, HNC0014. The molecular docking analysis suggested strong interactions between HNC0014 and oncogenic molecules; c-Met, STAT3, CD44, and PD-L1. Subsequently, we demonstrated that HNC0014 treatment suppressed HNSCC tumorigenic and expression of stemness markers; HNC0014 also reduced cancer-associated fibroblast (CAF) transformation by Exosp- and CAF-induced tumorigenic properties. HNC0014 treatment alone suppressed tumor growth in a cisplatin-resistant (SAS tumorspheres) mouse xenograft model and with higher inhibitory efficacy when combined with CDDP. More importantly, HNC0014 treatment significantly delayed tumor growth in a syngeneic mouse HNSCC model, elicited an antitumor immune profile, and reduced the total c-Met, STAT3, and their phosphorylated forms, PD-L1 and CD44, contents in serum exosomes. Collectively, our findings provide supports for HNC0014 as a multi-targeted immunotherapeutic lead compound for further development. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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17 pages, 883 KiB  
Article
Outcome of Targeted Therapy Recommendations for Metastatic and Recurrent Head and Neck Cancers
by Hossein Taghizadeh, Robert M. Mader, Leonhard Müllauer, Thorsten Fuereder, Alexandra Kautzky-Willer and Gerald W. Prager
Cancers 2020, 12(11), 3381; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113381 - 15 Nov 2020
Cited by 2 | Viewed by 2187
Abstract
Recurrent/metastatic (R/M) head and neck cancers bear a poor prognosis. In this analysis, we examined the efficacy and the outcome of targeted therapy recommendations based on the patients’ molecular tumor portrait after failure of all standard therapy options. In this single-center, real-world retrospective [...] Read more.
Recurrent/metastatic (R/M) head and neck cancers bear a poor prognosis. In this analysis, we examined the efficacy and the outcome of targeted therapy recommendations based on the patients’ molecular tumor portrait after failure of all standard therapy options. In this single-center, real-world retrospective analysis of our platform for precision medicine, we analyzed the molecular profile of 50 patients diagnosed with R/M head and neck cancer. Tumor samples of the patients were examined using next-generation sequencing panels of mutation hotspots, microsatellite instability (MSI) testing, and immunohistochemistry (IHC). In 31 cases (62.0% of all patients), a molecular-driven targeted therapy approach was recommended. Eventually, 14 patients (28%) received the suggested targeted therapy. Six of fourteen patients (43%) achieved stable disease conditions and four patients (29%) experienced a progressive disease. The median time to treatment failure was 2.8 months. Therapy recommendations were significantly more often issued for men (p = 0.037) than for women. This analysis demonstrated that precision medicine provided the basis for molecular-driven therapy recommendations in over half of the patients with advanced therapy refractory head and neck cancers, with significantly more therapy recommendations for men. Our analysis showed that although precision medicine approaches are implementable and feasible for the management of recurrent/metastatic head and neck cancers in daily clinical routine, there are major limitations and challenges that have to be overcome. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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13 pages, 3615 KiB  
Article
Evaluation of Carbon Ion Radiation-Induced Trismus in Head and Neck Tumors Using Dose-Volume Histograms
by Atsushi Musha, Hirofumi Shimada, Nobuteru Kubo, Hidemasa Kawamura, Naoko Okano, Yuhei Miyasaka, Hiro Sato, Katsuyuki Shirai, Jun-ichi Saitoh, Satoshi Yokoo, Kazuaki Chikamatsu and Tatsuya Ohno
Cancers 2020, 12(11), 3116; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113116 - 25 Oct 2020
Cited by 5 | Viewed by 1876
Abstract
Carbon ion radiotherapy (C-ion RT) provides a highly localized deposition of energy that can increase radiation doses to tumors while minimizing irradiation of adjacent normal tissues. For tumors located near the temporomandibular joint, C-ion RT-induced trismus may occur. However, the relationship between the [...] Read more.
Carbon ion radiotherapy (C-ion RT) provides a highly localized deposition of energy that can increase radiation doses to tumors while minimizing irradiation of adjacent normal tissues. For tumors located near the temporomandibular joint, C-ion RT-induced trismus may occur. However, the relationship between the carbon ion dose and the onset of trismus is unclear. In this prospective observational study, we assessed the trismus/carbon ion dose relationship using dose−volume histograms in 35 patients who received C-ion RT in their head and neck regions between 2010 and 2014. Trismus was evaluated in patients according to the Common Terminology Criteria for Adverse Events, version 4.0. All patients were treated with 57.6 or 64.0 Gy (relative biological effectiveness (RBE)) in 16 fractions, and the median follow-up time was 57 months. Grade 2 trismus was observed in six patients. The median onset time was 12 months. At maximum radiation doses, all masticatory muscles and coronoid processes, particularly the masseter muscle, were significantly different (p = 0.003). The contouring of the masseter muscle and coronoid process requires different treatment planning. The maximum radiation doses of the coronoid process can be proposed as a guideline for treatment planning, considering the ease of contouring in C-ion RT. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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19 pages, 4433 KiB  
Article
Comprehensive Exome Analysis of Immunocompetent Metastatic Head and Neck Cancer Models Reveals Patient Relevant Landscapes
by Hui Li, Hoi-Lam Ngan, Yuchen Liu, Helen Hoi Yin Chan, Peony Hiu Yan Poon, Chun Kit Yeung, Yibing Peng, Wai Yip Lam, Benjamin Xiaoyi Li, Yukai He and Vivian Wai Yan Lui
Cancers 2020, 12(10), 2935; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102935 - 12 Oct 2020
Cited by 4 | Viewed by 2799
Abstract
Immunocompetent metastatic head and neck cancer (HNC) models, although scarce, can help understanding cancer progression and therapy responses in vivo. Their comprehensive genome characterizations are essential for translational research. We first exome-sequenced the two most widely used spontaneous metastatic immunocompetent models, namely AT-84 [...] Read more.
Immunocompetent metastatic head and neck cancer (HNC) models, although scarce, can help understanding cancer progression and therapy responses in vivo. Their comprehensive genome characterizations are essential for translational research. We first exome-sequenced the two most widely used spontaneous metastatic immunocompetent models, namely AT-84 and SCC VII, followed by comprehensive genomic analyses with three prior-sequenced models (MOC2, MOC2-10, and 4MOSC2), together with patient tumors for utility assessment. AT-84 and SCC VII bear high HNC tumor resemblance regarding mutational signatures—Trp53, Fanconi anemia, and MAPK and PI3K pathway defects. Collectively, the five models harbor genetic aberrations across 10 cancer hallmarks and 14 signaling pathways and machineries (metabolic, epigenetic, immune evasion), to extents similar in patients. Immune defects in HLA-A (H2-Q10, H2-Q4, H2-Q7, and H2-K1), Pdcd1, Tgfb1, Il2ra, Il12a, Cd40, and Tnfrsf14 are identified. Invasion/metastatic genome analyses first highlight potential druggable ERBB4 and KRAS mutations, for advanced/metastatic oral cavity cancer, as well as known metastasis players (Muc5ac, Trem3, Trp53, and Ttn) frequently captured by all models. Notable immunotherapy and precision druggable targets (Pdcd1, Erbb4, Fgfr1, H/Kras, Jak1, and Map2k2) and three druggable hubs (RTK family, MAPK, and DNA repair pathways) are frequently represented by these models. Immunocompetent metastatic HNC models are worth developing to address therapy- and invasion/metastasis-related questions in host immunity contexts. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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18 pages, 2621 KiB  
Article
Downregulation of the DNA Repair Gene DDB2 by Arecoline Is through p53’s DNA-Binding Domain and Is Correlated with Poor Outcome of Head and Neck Cancer Patients with Betel Quid Consumption
by Yu-Chu Wang, Jau-Ling Huang, Ka-Wo Lee, Hsing-Han Lu, Yuan-Jen Lin, Long-Fong Chen, Chung-Sheng Wang, Yun-Chiao Cheng, Zih-Ting Zeng, Pei-Yi Chu and Chang-Shen Lin
Cancers 2020, 12(8), 2053; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082053 - 25 Jul 2020
Cited by 9 | Viewed by 2674
Abstract
Arecoline is the principal alkaloid in the areca nut, a component of betel quids (BQs), which are carcinogenic to humans. Epidemiological studies indicate that BQ-chewing contributes to the occurrence of head and neck cancer (HNC). Previously, we have reported that arecoline (0.3 mM) [...] Read more.
Arecoline is the principal alkaloid in the areca nut, a component of betel quids (BQs), which are carcinogenic to humans. Epidemiological studies indicate that BQ-chewing contributes to the occurrence of head and neck cancer (HNC). Previously, we have reported that arecoline (0.3 mM) is able to inhibit DNA repair in a p53-dependent pathway, but the underlying mechanism is unclear. Here we demonstrated that arecoline suppressed the expression of DDB2, which is transcriptionally regulated by p53 and is required for nucleotide excision repair (NER). Ectopic expression of DDB2 restored NER activity in arecoline-treated cells, suggesting that DDB2 downregulation was critical for arecoline-mediated NER inhibition. Mechanistically, arecoline inhibited p53-induced DDB2 promoter activity through the DNA-binding but not the transactivation domain of p53. Both NER and DDB2 promoter activities declined in the chronic arecoline-exposed cells, which were consistent with the downregulated DDB2 mRNA in BQ-associated HNC specimens, but not in those of The Cancer Genome Atlas (TCGA) cohort (no BQ exposure). Lower DDB2 mRNA expression was correlated with a poor outcome in HNC patients. These data uncover one of mechanisms underlying arecoline-mediated carcinogenicity through inhibiting p53-regulated DDB2 expression and DNA repair. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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14 pages, 1659 KiB  
Article
Macrophages in Oral Carcinomas: Relationship with Cancer Stem Cell Markers and PD-L1 Expression
by Faustino J. Suárez-Sánchez, Paloma Lequerica-Fernández, Julián Suárez-Canto, Juan P. Rodrigo, Tania Rodriguez-Santamarta, Francisco Domínguez-Iglesias, Juana M. García-Pedrero and Juan C. de Vicente
Cancers 2020, 12(7), 1764; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071764 - 02 Jul 2020
Cited by 36 | Viewed by 2898
Abstract
Tumor-associated macrophages (TAMs) can be polarized into antitumoral M1 and protumoral and immunosuppressive M2 macrophages. This study investigated the clinical relevance of TAM infiltration in oral squamous cell carcinoma (OSCC), evaluating CD68 (M1 and M2 macrophage marker) and CD163 expression (M2 macrophage marker) [...] Read more.
Tumor-associated macrophages (TAMs) can be polarized into antitumoral M1 and protumoral and immunosuppressive M2 macrophages. This study investigated the clinical relevance of TAM infiltration in oral squamous cell carcinoma (OSCC), evaluating CD68 (M1 and M2 macrophage marker) and CD163 expression (M2 macrophage marker) in the tumor nests and surrounding stroma. Immunohistochemical analysis of both stromal/tumoral CD68+ and CD163+ TAMs was performed in paraffin-embedded tissue specimens from 125 OSCC patients, and correlated with clinical data. Potential relationships with the expression of cancer stem cell (CSC) markers and PD-L1 in the tumors were also assessed. Stromal CD163+ infiltration was significantly associated with the tumor location in the tongue, and stromal and tumoral CD68+ and CD163+-infiltrating TAMs were more abundant in nonsmokers and non-alcohol-drinkers. Strikingly, this study uncovers an inverse relationship between CD68+ and CD163+ TAMs and CSC marker expression (NANOG and SOX2) in OSCC. High infiltration of CD163+ TAMs in both tumor and stroma was strongly and significantly correlated with the absence of NANOG expression. Moreover, infiltration of both CD68+ and CD163+ TAMs was also significantly associated with high tumor expression of PD-L1. Our results suggest that there is a link between TAM infiltration and immune escape in OSCC. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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20 pages, 3201 KiB  
Article
Tumor Biomarkers for the Prediction of Distant Metastasis in Head and Neck Squamous Cell Carcinoma
by Salvatore Alfieri, Andrea Carenzo, Francesca Platini, Mara S. Serafini, Federica Perrone, Donata Galbiati, Andrea P. Sponghini, Roberta Depenni, Andrea Vingiani, Pasquale Quattrone, Edoardo Marchesi, Maria F. Iannó, Arianna Micali, Elisa Mancinelli, Ester Orlandi, Sara Marceglia, Laura D. Locati, Lisa Licitra, Paolo Bossi and Loris De Cecco
Cancers 2020, 12(4), 922; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040922 - 09 Apr 2020
Cited by 11 | Viewed by 3458
Abstract
Distant metastases (DM) in head and neck squamous cell carcinoma (HNSCC) remain a challenge as treatment options are limited. To identify biomarkers predictive of DM in primary tumors (PT), gene expression profiling was performed in PT from patients who did, or did not [...] Read more.
Distant metastases (DM) in head and neck squamous cell carcinoma (HNSCC) remain a challenge as treatment options are limited. To identify biomarkers predictive of DM in primary tumors (PT), gene expression profiling was performed in PT from patients who did, or did not develop DM (T-with and T-without, n = 25 and 24, respectively), and in matched DM. A total of 185 and 42 differentially expressed genes were identified in the T-with vs. T-without and the T-with vs. DM comparisons, respectively. The intersection between these two comparisons identified COX7A1 and TBX5 as common genes. In three independent datasets, both genes were able to significantly distinguish patients according to their DM-free survival. By functional biological analyses, the T-without group showed enrichment in immune-response pathways, whereas the T-with group showed an enrichment in B-plasma cells and Tregs. Increased enrichment of proliferation-related pathways was observed in the T-with group compared with that in the DM group. Further comparisons with/without DM are needed to confirm these data in order to improve clinical management of HNSCC. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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16 pages, 2918 KiB  
Article
Karyopherin-β1 Regulates Radioresistance and Radiation-Increased Programmed Death-Ligand 1 Expression in Human Head and Neck Squamous Cell Carcinoma Cell Lines
by Masaharu Hazawa, Hironori Yoshino, Yuta Nakagawa, Reina Shimizume, Keisuke Nitta, Yoshiaki Sato, Mariko Sato, Richard W. Wong and Ikuo Kashiwakura
Cancers 2020, 12(4), 908; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040908 - 08 Apr 2020
Cited by 9 | Viewed by 4010
Abstract
Nuclear transport receptors, such as karyopherin-β1 (KPNB1), play important roles in the nuclear-cytoplasmic transport of macromolecules. Recent evidence indicates the involvement of nuclear transport receptors in the progression of cancer, making these receptors promising targets for the treatment of cancer. Here, we investigated [...] Read more.
Nuclear transport receptors, such as karyopherin-β1 (KPNB1), play important roles in the nuclear-cytoplasmic transport of macromolecules. Recent evidence indicates the involvement of nuclear transport receptors in the progression of cancer, making these receptors promising targets for the treatment of cancer. Here, we investigated the anticancer effects of KPNB1 blockage or in combination with ionizing radiation on human head and neck squamous cell carcinoma (HNSCC). HNSCC cell line SAS and Ca9-22 cells were used in this study. Importazole, an inhibitor of KPNB1, or knockdown of KPNB1 by siRNA transfection were applied for the blockage of KPNB1 functions. The roles of KPNB1 on apoptosis induction and cell surface expression levels of programmed death-ligand 1 (PD-L1) in irradiated HNSCC cells were investigated. The major findings of this study are that (i) blockage of KPNB1 specifically enhanced the radiation-induced apoptosis and radiosensitivity of HNSCC cells; (ii) importazole elevated p53-upregulated modulator of apoptosis (PUMA) expression via blocking the nuclear import of SCC-specific oncogene ΔNp63 in HNSCC cells; and (iii) blockage of KPNB1 attenuated the upregulation of cell surface PD-L1 expression on irradiated HNSCC cells. Taken together, these results suggest that co-treatment with KPNB1 blockage and ionizing radiation is a promising strategy for the treatment of HNSCC. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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19 pages, 3568 KiB  
Article
Dual Targeting of the p38 MAPK-HO-1 Axis and cIAP1/XIAP by Demethoxycurcumin Triggers Caspase-Mediated Apoptotic Cell Death in Oral Squamous Cell Carcinoma Cells
by Ming-Hsien Chien, Wei-En Yang, Yi-Chieh Yang, Chia-Chi Ku, Wei-Jiunn Lee, Meng-Ying Tsai, Chiao-Wen Lin and Shun-Fa Yang
Cancers 2020, 12(3), 703; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030703 - 16 Mar 2020
Cited by 27 | Viewed by 4480
Abstract
Demethoxycurcumin (DMC) is a curcumin analogue with better stability and higher aqueous solubility than curcumin after oral ingestion and has the potential to treat diverse cancers, including oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the anticancer effects [...] Read more.
Demethoxycurcumin (DMC) is a curcumin analogue with better stability and higher aqueous solubility than curcumin after oral ingestion and has the potential to treat diverse cancers, including oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the anticancer effects and underlying mechanisms of DMC against OSCC. We found that DMC suppressed cell proliferation via simultaneously inducing G2/M-phase arrest and cell apoptosis. Mechanistic investigations found that the downregulation of cellular IAP 1 (cIAP1)/X-chromosome-linked IAP (XIAP) and upregulation of heme oxygenase-1 (HO-1) were critical for DMC-induced caspase-8/-9/-3 activation and apoptotic cell death. Moreover, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK)1/2 were activated by DMC treatment in OSCC cells, and only the inhibition of p38 MAPK significantly abolished DMC-induced HO-1 expression and caspase-8/-9/-3 activation. The analyses of clinical datasets revealed that patients with head and neck cancers expressing high HO-1 and low cIAP1 had the most favorable prognoses. Furthermore, a combinatorial treatment of DMC with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib, significantly enhanced the inhibitory effect of gefitinib on the proliferation of OSCC cells. Overall, the current study supported a role for DCM as part of a therapeutic approach for OSCC through suppressing IAPs and activating the p38-HO-1 axis. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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16 pages, 2952 KiB  
Article
MR and CT Imaging of the Normal Eyelid and its Application in Eyelid Tumors
by Teresa A. Ferreira, Carolina F. Pinheiro, Paulo Saraiva, Myriam G. Jaarsma-Coes, Sjoerd G. Van Duinen, Stijn W. Genders, Marina Marinkovic and Jan-Willem M. Beenakker
Cancers 2020, 12(3), 658; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030658 - 12 Mar 2020
Cited by 8 | Viewed by 7110
Abstract
T-staging of most eyelid malignancies includes the assessment of the integrity of the tarsal plate and orbital septum, which are not clinically accessible. Given the contribution of MRI in the characterization of orbital tumors and establishing their relations to nearby structures, we assessed [...] Read more.
T-staging of most eyelid malignancies includes the assessment of the integrity of the tarsal plate and orbital septum, which are not clinically accessible. Given the contribution of MRI in the characterization of orbital tumors and establishing their relations to nearby structures, we assessed its value in identifying different eyelid structures in 38 normal eyelids and evaluating tumor extension in three cases of eyelid tumors. As not all patients can receive an MRI, we evaluated those same structures on CT and compared both results. All eyelid structures were identified on MRI and CT, except for the conjunctiva on both techniques and for the tarsal muscles on CT. Histopathology confirmed the MRI findings of orbital septum invasion in one patient, and the MRI findings of intact tarsus and orbital septum in another patient. Histopathology could not confirm or exclude tarsal invasion seen on MRI on two patients. Although imaging the eyelid is challenging, the identification of most eyelid structures is possible with MRI and, to a lesser extent, with CT and can, therefore, have an important contribution to the T-staging of eyelid tumors, which may improve treatment planning and outcome. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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29 pages, 3481 KiB  
Review
Cancer and Stress: Does It Make a Difference to the Patient When These Two Challenges Collide?
by Anem Iftikhar, Mohammad Islam, Simon Shepherd, Sarah Jones and Ian Ellis
Cancers 2021, 13(2), 163; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13020163 - 06 Jan 2021
Cited by 20 | Viewed by 6094
Abstract
A single head and neck Cancer (HNC) is a globally growing challenge associated with significant morbidity and mortality. The diagnosis itself can affect the patients profoundly let alone the complex and disfiguring treatment. The highly important functions of structures of the head and [...] Read more.
A single head and neck Cancer (HNC) is a globally growing challenge associated with significant morbidity and mortality. The diagnosis itself can affect the patients profoundly let alone the complex and disfiguring treatment. The highly important functions of structures of the head and neck such as mastication, speech, aesthetics, identity and social interactions make a cancer diagnosis in this region even more psychologically traumatic. The emotional distress engendered as a result of functional and social disruption is certain to negatively affect health-related quality of life (HRQoL). The key biological responses to stressful events are moderated through the combined action of two systems, the hypothalamus–pituitary–adrenal axis (HPA) which releases glucocorticoids and the sympathetic nervous system (SNS) which releases catecholamines. In acute stress, these hormones help the body to regain homeostasis; however, in chronic stress their increased levels and activation of their receptors may aid in the progression of cancer. Despite ample evidence on the existence of stress in patients diagnosed with HNC, studies looking at the effect of stress on the progression of disease are scarce, compared to other cancers. This review summarises the challenges associated with HNC that make it stressful and describes how stress signalling aids in the progression of cancer. Growing evidence on the relationship between stress and HNC makes it paramount to focus future research towards a better understanding of stress and its effect on head and neck cancer. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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21 pages, 1683 KiB  
Review
The Mismatch Repair System (MMR) in Head and Neck Carcinogenesis and Its Role in Modulating the Response to Immunotherapy: A Critical Review
by Maria Cilona, Luca Giovanni Locatello, Luca Novelli and Oreste Gallo
Cancers 2020, 12(10), 3006; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12103006 - 16 Oct 2020
Cited by 15 | Viewed by 6112
Abstract
The mismatch repair (MMR) system has a major role in the detection and correction of DNA replication errors, resulting from DNA polymerase slippage or nucleotides misincorporation. Specific inherited/acquired alterations or epigenetic inactivation of MMR genes are associated with microsatellite instability (MSI): the loss [...] Read more.
The mismatch repair (MMR) system has a major role in the detection and correction of DNA replication errors, resulting from DNA polymerase slippage or nucleotides misincorporation. Specific inherited/acquired alterations or epigenetic inactivation of MMR genes are associated with microsatellite instability (MSI): the loss of crucial function in repairing DNA alterations can promote carcinogenesis by favoring the accumulation of thousands of mutations in a broad spectrum of different anatomic sites such as colon, stomach, prostate, esophagus, endometrium, lung and head and neck. Recent extensive data suggest that tumor mutational burden strongly correlates with a clinical response to immunotherapy using checkpoint inhibitors and this response is influenced by MMR deficiency in a wide range of human solid cancers. In this context, few data about this crucial point are available for head and neck cancer (HNC). In this review, we discuss the role of MMR alterations and the resulting MSI in HNC pathogenesis. Furthermore, by summarizing the clinical available data on how they influence the progression of precancerous lesions and the risk of recurrence or second primary tumors, we want to define the current role of MSI in the management of HNC. Finally, we analyze the complex interaction between cancer cells and the immune system addressing the data now available about a potential correlation between microsatellite instability and immunotherapy response in HNC. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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25 pages, 1755 KiB  
Review
Regulation of NFκB Signalling by Ubiquitination: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma?
by Ethan L. Morgan, Zhong Chen and Carter Van Waes
Cancers 2020, 12(10), 2877; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102877 - 07 Oct 2020
Cited by 21 | Viewed by 3332
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with over 600,000 cases per year. The primary causes for HNSCC include smoking and alcohol consumption, with an increasing number of cases attributed to infection with Human Papillomavirus (HPV). [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with over 600,000 cases per year. The primary causes for HNSCC include smoking and alcohol consumption, with an increasing number of cases attributed to infection with Human Papillomavirus (HPV). The treatment options for HNSCC currently include surgery, radiotherapy, and/or platinum-based chemotherapeutics. Cetuximab (targeting EGFR) and Pembrolizumab (targeting PD-1) have been approved for advanced stage, recurrent, and/or metastatic HNSCC. Despite these advances, whilst HPV+ HNSCC has a 3-year overall survival (OS) rate of around 80%, the 3-year OS for HPV− HNSCC is still around 55%. Aberrant signal activation of transcription factor NFκB plays an important role in the pathogenesis and therapeutic resistance of HNSCC. As an important mediator of inflammatory signalling and the immune response to pathogens, the NFκB pathway is tightly regulated to prevent chronic inflammation, a key driver of tumorigenesis. Here, we discuss how NFκB signalling is regulated by the ubiquitin pathway and how this pathway is deregulated in HNSCC. Finally, we discuss the current strategies available to target the ubiquitin pathway and how this may offer a potential therapeutic benefit in HNSCC. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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18 pages, 1633 KiB  
Review
Role of Oral Bacteria in the Development of Oral Squamous Cell Carcinoma
by Qinyang Li, Yao Hu, Xuedong Zhou, Shiyu Liu, Qi Han and Lei Cheng
Cancers 2020, 12(10), 2797; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102797 - 29 Sep 2020
Cited by 27 | Viewed by 3717
Abstract
Oral squamous cell carcinoma (OSCC) is an invasive epithelial neoplasm that is influenced by various risk factors, with a low survival rate and an increasing death rate. In the past few years, with the verification of the close relationship between different types of [...] Read more.
Oral squamous cell carcinoma (OSCC) is an invasive epithelial neoplasm that is influenced by various risk factors, with a low survival rate and an increasing death rate. In the past few years, with the verification of the close relationship between different types of cancers and the microbiome, research has focused on the compositional changes of oral bacteria and their role in OSCC. Generally, oral bacteria can participate in OSCC development by promoting cell proliferation and angiogenesis, influencing normal apoptosis, facilitating invasion and metastasis, and assisting cancer stem cells. The study findings on the association between oral bacteria and OSCC may provide new insight into methods for early diagnosis and treatment development. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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16 pages, 316 KiB  
Review
Can Bioelectrical Impedance Analysis and BMI Be a Prognostic Tool in Head and Neck Cancer Patients? A Review of the Evidence
by Maria Mantzorou, Maria Tolia, Antigoni Poultsidi, Eleni Pavlidou, Sousana K. Papadopoulou, Dimitrios Papandreou and Constantinos Giaginis
Cancers 2020, 12(3), 557; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030557 - 28 Feb 2020
Cited by 6 | Viewed by 2525
Abstract
Background: Malnutrition can significantly affect disease progression and patient survival. The efficiency of weight loss and bioimpedance analysis (BIA)-derived measures in the evaluation of malnutrition, and disease progression and prognosis in patients with head and neck cancer (HNC) are an important area of [...] Read more.
Background: Malnutrition can significantly affect disease progression and patient survival. The efficiency of weight loss and bioimpedance analysis (BIA)-derived measures in the evaluation of malnutrition, and disease progression and prognosis in patients with head and neck cancer (HNC) are an important area of research. Method: The PubMed database was thoroughly searched, using relative keywords in order to identify clinical trials that investigated the role of BIA-derived measures and weight loss on the disease progression and prognosis of patients with HNC. Twenty-seven studies met the criteria. More specifically, six studies examined the prognostic role of the tissue electrical properties in HNC patients; five examined the role of the tissue electrical properties on identifying malnutrition; four studies looked at the changes in the tissue electrical properties of HNC patients; and 12 examined the prognostic role of weight loss on survival and/or treatment outcomes. Results: Several studies have investigated the role of nutritional status tools on prognosis in HNC patients. Current studies investigating the potential of BIA-derived raw data have shown that phase angle (PA) and capacitance of the cell membrane may be considered prognostic factors of survival. Weight loss may be a prognostic factor for treatment toxicity and survival, despite some conflicting evidence. Conclusions: Further studies are recommended to clarify the role of BIA-derived measures on patients’ nutritional status and the impact of PA on clinical outcomes as well as the prognostic role of weight loss. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
19 pages, 3375 KiB  
Review
The Role of Carcinogenesis-Related Biomarkers in the Wnt Pathway and Their Effects on Epithelial–Mesenchymal Transition (EMT) in Oral Squamous Cell Carcinoma
by Yunpeng Bai, Jingjing Sha and Takahiro Kanno
Cancers 2020, 12(3), 555; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030555 - 28 Feb 2020
Cited by 38 | Viewed by 4591
Abstract
As oral squamous cell carcinoma (OSCC) can develop from potentially malignant disorders (PMDs), it is critical to develop methods for early detection to improve the prognosis of patients. Epithelial–mesenchymal transition (EMT) plays an important role during tumor progression and metastasis. The Wnt signaling [...] Read more.
As oral squamous cell carcinoma (OSCC) can develop from potentially malignant disorders (PMDs), it is critical to develop methods for early detection to improve the prognosis of patients. Epithelial–mesenchymal transition (EMT) plays an important role during tumor progression and metastasis. The Wnt signaling pathway is an intercellular pathway in animals that also plays a fundamental role in cell proliferation and regeneration, and in the function of many cell or tissue types. Specific components of master regulators such as epithelial cadherin (E-cadherin), Vimentin, adenomatous polyposis coli (APC), Snail, and neural cadherin (N-cadherin), which are known to control the EMT process, have also been implicated in the Wnt cascade. Here, we review recent findings on the Wnt signaling pathway and the expression mechanism. These regulators are known to play roles in EMT and tumor progression, especially in OSCC. Characterizing the mechanisms through which both EMT and the Wnt pathway play a role in these cellular pathways could increase our understanding of the tumor genesis process and may allow for the development of improved therapeutics for OSCC. Full article
(This article belongs to the Special Issue Head and Neck Cancers)
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