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Molecular Mechanisms and Pathophysiology of Head and Neck Diseases

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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 2023) | Viewed by 17886

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Special Issue Editors

Dr. Urs Müller-Richter

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Guest Editor

Oral and Maxillofacial Plastic Surgery, Universitätsklinikum Würzburg, 97080 Wurzburg, Germany
Interests: head and neck cancer; cancer metabolism; clinical nutrition; cancer diagnosis and treatment

Dr. Stefan Hartmann

E-Mail Website
Guest Editor

Department of Oral and Maxillofacial Plastic Surgery, University Hospital Würzburg, 97070 Würzburg, Germany
Interests: cancer surgery; CAD/CAM; digital planning; imaging; dental technology; artificial intelligence
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Research in the whole head and neck area is a vivid field and important contributions in recent years have led to changes in the diagnosis, treatment, and follow up of many diseases.

Today’s medicine aims at a more personalized approach. To this end, understanding of molecular mechanisms is crucial and can serve as the basis for new diagnostic and therapeutic approaches. in long term, this can ultimately help to improve patient care. Therefore, the aim of this Special Issue is to illustrate and discuss molecular mechanisms and underlying pathophysiology in major fields of head and neck pathology. This typically consists of, but is not limited to, cancer, craniofacial malformations and developmental disorders, infections, and hard and soft tissue wound healing.

Original research articles, reviews, and communications related to the above-mentioned topics are welcomed.

Dr. Urs Müller-Richter
Dr. Stefan Hartmann
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

head and neck
craniofacial
oral cancer

Published Papers (7 papers)

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Research

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24 pages, 6297 KiB

Open AccessArticle

KDM5D Histone Demethylase Identifies Platinum-Tolerant Head and Neck Cancer Cells Vulnerable to Mitotic Catastrophe

by Tsung-Ming Chen, Chih-Ming Huang, Syahru Agung Setiawan, Ming-Shou Hsieh, Chih-Chi Sheen and Chi-Tai Yeh

Int. J. Mol. Sci. 2023, 24(6), 5310; https://doi.org/10.3390/ijms24065310 - 10 Mar 2023

Cited by 2 | Viewed by 1857

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a major contributor to cancer incidence globally and is currently managed by surgical resection followed by adjuvant chemoradiotherapy. However, local recurrence is the major cause of mortality, indicating the emergence of drug-tolerant persister cells. A specific histone demethylase, namely lysine-specific demethylase 5D (KDM5D), is overexpressed in diverse types of cancers and involved in cancer cell cycle regulation. However, the role of KDM5D in the development of cisplatin-tolerant persister cells remains unexplored. Here, we demonstrated that KDM5D contributes to the development of persister cells. Aurora Kinase B (AURKB) disruption affected the vulnerability of persister cells in a mitotic catastrophe–dependent manner. Comprehensive in silico, in vitro, and in vivo experiments were performed. KDM5D expression was upregulated in HNSCC tumor cells, cancer stem cells, and cisplatin-resistant cells with biologically distinct signaling alterations. In an HNSCC cohort, high KDM5D expression was associated with a poor response to platinum treatment and early disease recurrence. KDM5D knockdown reduced the tolerance of persister cells to platinum agents and caused marked cell cycle deregulation, including the loss of DNA damage prevention, and abnormal mitosis-enhanced cell cycle arrest. By modulating mRNA levels of AURKB, KDM5D promoted the generation of platinum-tolerant persister cells in vitro, leading to the identification of the KDM5D/AURKB axis, which regulates cancer stemness and drug tolerance of HNSCC. Treatment with an AURKB inhibitor, namely barasertib, resulted in a lethal consequence of mitotic catastrophe in HNSCC persister cells. The cotreatment of cisplatin and barasertib suppressed tumor growth in the tumor mouse model. Thus, KDM5D might be involved in the development of persister cells, and AURKB disruption can overcome tolerance to platinum treatment in HNSCC. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Head and Neck Diseases)

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11 pages, 1558 KiB

Open AccessArticle

Protein-Based Oncopanel as Addition to Target Sequencing in Head and Neck Squamous Cell Carcinoma to Individualize Treatment Decisions

by Adrian von Witzleben, Urs Müller-Richter, Katja Maurus, Stephanie Brändlein, Marie-Nicole Theodoraki, Cornelia Brunner, Simon Laban, Jochen Lennerz, Peter Möller, Thomas K. Hoffmann, Johannes Doescher and Patrick J. Schuler

Int. J. Mol. Sci. 2022, 23(24), 15835; https://doi.org/10.3390/ijms232415835 - 13 Dec 2022

Viewed by 1388

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of cancers and patients have limited therapy options if primary treatment fails. Therefore, additional information about the biology of the tumor is essential. Here we performed a feasibility study of concurrently applying two precision diagnostic tools in a consecutive series of HNSCC patients. We analyzed tumor samples of 31 patients using a genomic (oncomine) and a proteomic, immunohistochemical approach (oncopanel) and compared the result, also in the focus on their overlapping therapeutical targets. We found no strong correlation between the two approaches and observed a higher proportion of marker expression for the immunohistochemical panel. However, both panels show in our HNSCC cohort distinct patterns with druggable targets. The data suggest that both approaches complement one another and can be applied side-by-side to identify the best targets for the development of individual treatment options for HNSCC patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Head and Neck Diseases)

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13 pages, 12706 KiB

Open AccessArticle

Activation of Mast-Cell-Derived Chymase in the Lacrimal Glands of Patients with IgG4-Related Ophthalmic Disease

by Yasushi Fujita, Denan Jin, Masashi Mimura, Yohei Sato, Shinji Takai and Teruyo Kida

Int. J. Mol. Sci. 2022, 23(5), 2556; https://doi.org/10.3390/ijms23052556 - 25 Feb 2022

Cited by 2 | Viewed by 1407

Abstract

The purpose of this present study was to investigate the distribution and expression of chymase in the lacrimal glands (LGs) of patients afflicted with IgG4-related ophthalmic disease (IgG4-ROD). LGs from patients with severe canalicular obstruction were considered the control group. Toluidine blue staining confirmed a significant increase in the number of mast cells in the LGs obtained from the IgG4-ROD patients. In addition, immunostaining of serial sections from the LGs showed a significant increase in the number of chymase-positive cells and tryptase-positive cells in the IgG4-ROD LGs compared to the normal control LGs. The mRNA expression of chymase, tryptase, TGF-β1, and collagen-I tended to increase in the IgG4-ROD LGs. Immunostaining of vimentin and α-smooth muscle actin (α-SMA) showed that myofibroblasts were the main cellular components in severely fibrotic regions of LGs in patients with IgG4-ROD. Linear regression analyses on the number of mast cells, chymase-positive cells, and tryptase-positive cells revealed significant positive correlations between those respective cells. Our findings suggest that chymase may play a role in the fibrotic disorder of IgG4-ROD LGs through the regulation of TGF-β1 activation and collagen-I deposition, and that it may be a therapeutic target for patients afflicted with IgG4-ROD. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Head and Neck Diseases)

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16 pages, 4585 KiB

Open AccessArticle

EVI1 Promotes the Proliferation and Invasive Properties of Human Head and Neck Squamous Cell Carcinoma Cells

by Alexander Michael Grandits, Sophie Bromberger, Gerwin Heller, Barbara Andrea Reinoehl, Erwin Tomasich, Klaudia Schossleitner, Anna Sophie Berghoff, Thorsten Fuereder and Rotraud Wieser

Int. J. Mol. Sci. 2022, 23(3), 1050; https://doi.org/10.3390/ijms23031050 - 19 Jan 2022

Cited by 3 | Viewed by 2051

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a frequent malignancy with a poor prognosis. So far, the EGFR inhibitor cetuximab is the only approved targeted therapy. A deeper understanding of the molecular and genetic basis of HNSCC is needed to identify additional targets for rationally designed, personalized therapeutics. The transcription factor EVI1, the major product of the MECOM locus, is an oncoprotein with roles in both hematological and solid tumors. In HNSCC, high EVI1 expression was associated with an increased propensity to form lymph node metastases, but its effects in this tumor entity have not yet been determined experimentally. We therefore overexpressed or knocked down EVI1 in several HNSCC cell lines and determined the impact of these manipulations on parameters relevant to tumor growth and invasiveness, and on gene expression patterns. Our results revealed that EVI1 promoted the proliferation and migration of HNSCC cells. Furthermore, it augmented tumor spheroid formation and the ability of tumor spheroids to displace an endothelial cell layer. Finally, EVI1 altered the expression of numerous genes in HNSCC cells, which were enriched for Gene Ontology terms related to its cellular functions. In summary, EVI1 represents a novel oncogene in HNSCC that contributes to cellular proliferation and invasiveness. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Head and Neck Diseases)

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Review

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17 pages, 2682 KiB

Open AccessReview

‘Toxic Masculinity’: What Is Known about the Role of Androgen Receptors in Head and Neck Squamous Cell Carcinoma

by Josipa Čonkaš, Maja Sabol and Petar Ozretić

Int. J. Mol. Sci. 2023, 24(4), 3766; https://doi.org/10.3390/ijms24043766 - 13 Feb 2023

Cited by 1 | Viewed by 2424

Abstract

Head and neck squamous cell carcinoma (HNSCC), the most prevalent cancer in the head and neck region, develops from the mucosal epithelium of the upper aerodigestive tract. Its development directly correlates with alcohol and/or tobacco consumption and infection with human papillomavirus. Interestingly, the relative risk for HNSCC is up to five times higher in males, so it is considered that the endocrine microenvironment is another risk factor. A gender-specific risk for HNSCC suggests either the existence of specific risk factors that affect only males or that females have defensive hormonal and metabolic features. In this review, we summarized the current knowledge about the role of both nuclear and membrane androgen receptors (nAR and mARs, respectively) in HNSCC. As expected, the significance of nAR is much better known; it was shown that increased nAR expression was observed in HNSCC, while treatment with dihydrotestosterone increased proliferation, migration, and invasion of HNSCC cells. For only three out of five currently known mARs—TRPM8, CaV1.2, and OXER1—it was shown either their increased expression in various types of HNSCC or that their increased activity enhanced the migration and invasion of HNSCC cells. The primary treatments for HNSCC are surgery and radiotherapy, but targeted immunotherapies are on the rise. On the other hand, given the evidence of elevated nAR expression in HNSCC, this receptor represents a potential target for antiandrogen therapy. Moreover, there is still plenty of room for further examination of mARs’ role in HNSCC diagnosis, prognosis, and treatment. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Head and Neck Diseases)

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29 pages, 880 KiB

Open AccessReview

DNA Methylation as a Diagnostic, Prognostic, and Predictive Biomarker in Head and Neck Cancer

by Galateia Liouta, Maria Adamaki, Antonis Tsintarakis, Panagiotis Zoumpourlis, Anastasia Liouta, Sofia Agelaki and Vassilis Zoumpourlis

Int. J. Mol. Sci. 2023, 24(3), 2996; https://doi.org/10.3390/ijms24032996 - 03 Feb 2023

Cited by 5 | Viewed by 2384

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a term collectively used to describe all cancers that develop in the oral and nasal cavities, the paranasal sinuses, the salivary glands, the pharynx, and the larynx. The majority (75%) of all newly diagnosed cases are observed in patients with locally advanced and aggressive disease, associated with significant relapse rates (30%) and poor prognostic outcomes, despite advances in multimodal treatment. Consequently, there is an unmet need for the identification and application of tools that would enable diagnosis at the earliest possible stage, accurately predict prognostic outcomes, contribute to the timely detection of relapses, and aid in the decision for therapy selection. Recent evidence suggests that DNA methylation can alter the expression of genes in a way that it favors tumorigenesis and tumor progression in HNSCC, and therefore represents a potential source for biomarker identification. This study summarizes the current knowledge on how abnormally methylated DNA profiles in HNSCC patients may contribute to the pathogenesis of HNSCC and designate the methylation patterns that have the potential to constitute clinically valuable biomarkers for achieving significant advances in the management of the disease and for improving survival outcomes in these patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Head and Neck Diseases)

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15 pages, 1293 KiB

Open AccessReview

Ocular Ischemic Syndrome and Its Related Experimental Models

by Deokho Lee, Yohei Tomita, Lizhu Yang, Kazuno Negishi and Toshihide Kurihara

Int. J. Mol. Sci. 2022, 23(9), 5249; https://doi.org/10.3390/ijms23095249 - 08 May 2022

Cited by 10 | Viewed by 5665

Abstract

Ocular ischemic syndrome (OIS) is one of the severe ocular disorders occurring from stenosis or occlusion of the carotid arteries. As the ophthalmic artery is derived from the branch of the carotid artery, stenosis or occlusion of the carotid arteries could induce chronic ocular hypoperfusion, finally leading to the development of OIS. To date, the pathophysiology of OIS is still not clearly unraveled. To better explore the pathophysiology of OIS, several experimental models have been developed in rats and mice. Surgical occlusion or stenosis of common carotid arteries or internal carotid arteries was conducted bilaterally or unilaterally for model development. In this regard, final ischemic outcomes in the eye varied depending on the surgical procedure, even though similar findings on ocular hypoperfusion could be observed. In the current review, we provide an overview of the pathophysiology of OIS from various experimental models, as well as several clinical cases. Moreover, we cover the status of current therapies for OIS along with promising preclinical treatments with recent advances. Our review will enable more comprehensive therapeutic approaches to prevent the development and/or progression of OIS. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Head and Neck Diseases)

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