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Frontiers in Oral Cancer—Basic and Clinical Sciences
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Frontiers in Oral Cancer—Basic and Clinical Sciences

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Dentistry, Oral Surgery and Oral Medicine".

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 31068

Special Issue Editor

Dr. Takanori Eguchi

E-Mail Website
Guest Editor
Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan
Interests: cellular and molecular biology; intercellular communication; extracellular vesicles; tumoroids; organoids; 3D culture systems; gene regulation; non-coding RNA; omics; moonlighting proteins; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oral cancers such as tongue cancer, buccal cancer, and gingival cancer are often human papilloma virus-negative oral squamous cell carcinoma [HPV (-) OSCC], thus distinguished from other HPV (+) head and neck cancers in genotypes, epigenotypes, and phenotypes. The most significant risk factors of oral cancers have been known to be tobacco and smoking in combination with alcohol as a synergistic higher risk, although oral sex may be another risk factor. Because the sites of primary lesions are exposed to the oral cavity, oral cancers are accessible in diagnosis and therapeutics, although metastasis to neck lymph nodes, lung, and other organs is correlated with poor prognosis in patients suffering from OSCC. Surgery, chemotherapies, and radiation therapy have been standards of care (SOC), while super-selective intra-arterial chemotherapy, immunotherapies, and potential photo-immunotherapy have been recently tried. Further, liquid biopsy of saliva has been investigated, in which extracellular vesicles such as exosomes, cell-free DNA (cfDNA), small RNA such as microRNA, proteins, and metabolites are attractive analytes to develop prognostic and diagnostic biomarkers. Metastasis and recurrence in oral cancer can be due to therapy resistance, anti-immune resistance caused by oral cancer stem cells (CSC), also known as cancer-initiating cells (CIC), epithelial–mesenchymal transition (EMT), and malignancy in the tumor microenvironment. Therefore, researchers and clinicians in the field of oral cancer are encouraged to submit an original article or a review to the Journal of Clinical Medicine Special Issue “Frontiers in Basic and Clinical Science of Oral Cancer.”

Dr. Takanori Eguchi
Guest Editor

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. Journal of Clinical Medicine 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 2600 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

  • oral cancer/head and neck cancer/squamous cell carcinoma
  • biomarker/diagnosis
  • therapy/treatment
  • tumor microenvironment and tumor immunology
  • extracellular vesicles and exosome
  • liquid biopsy and saliva
  • cancer stem cell
  • cancer-initiating cell
  • epithelial–mesenchymal transition

Published Papers (9 papers)

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Editorial

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5 pages, 191 KiB  
Editorial
Organoids and Liquid Biopsy in Oral Cancer Research
by Takanori Eguchi
J. Clin. Med. 2020, 9(11), 3701; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9113701 - 18 Nov 2020
Cited by 3 | Viewed by 2275
Abstract
To promote the newest discoveries in oral cancer research, a special issue “Frontiers in Oral Cancer—Basic and Clinical Sciences” in the Journal of Clinical Medicine (JCM) was opened from September 2019 to April 2020 [...] Full article
(This article belongs to the Special Issue Frontiers in Oral Cancer—Basic and Clinical Sciences)

Research

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12 pages, 2428 KiB  
Article
CDK 4/6 Inhibition Overcomes Acquired and Inherent Resistance to PI3Kα Inhibition in Pre-Clinical Models of Head and Neck Squamous Cell Carcinoma
by Eric Remer, Mai Badarni, Elad Hikri, Avraham Dayan, Lirit Levi, Aron Popovtzer, Muhammed Iraqi, Angel Porgador, Ben-Zion Joshua, Gideon Bachar, Moshe Elkabets, Maurizio Scaltriti and Aviram Mizrachi
J. Clin. Med. 2020, 9(10), 3214; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9103214 - 07 Oct 2020
Cited by 5 | Viewed by 2718
Abstract
Activating alterations in PIK3CA, the gene coding for the catalytic subunit of phosphoinositide-3-kinase (PI3K), are prevalent in head and neck squamous cell carcinoma (HNSCC) and thought to be one of the main drivers of these tumors. However, early clinical trials on PI3K [...] Read more.
Activating alterations in PIK3CA, the gene coding for the catalytic subunit of phosphoinositide-3-kinase (PI3K), are prevalent in head and neck squamous cell carcinoma (HNSCC) and thought to be one of the main drivers of these tumors. However, early clinical trials on PI3K inhibitors (PI3Ki) have been disappointing due to the limited durability of the activity of these drugs. To investigate the resistance mechanisms to PI3Ki and attempt to overcome them, we conducted a molecular-based study using both HNSCC cell lines and patient-derived xenografts (PDXs). We sought to simulate and dissect the molecular pathways that come into play in PIK3CA-altered HNSCC treated with isoform-specific PI3Ki (BYL719, GDC0032). In vitro assays of cell viability and protein expression indicate that activation of the mTOR and cyclin D1 pathways is associated with resistance to PI3Ki. Specifically, in BYL719-resistant cells, BYL719 treatment did not induce pS6 and pRB inhibition as detected in BYL719-sensitive cells. By combining PI3Ki with either mammalian target of rapamycin complex 1 (mTORC1) or cyclin D1 kinase (CDK) 4/6 specific inhibitors (RAD001 and abemaciclib, respectively), we were able to overcome the acquired resistance. Furthermore, we found that PI3Ki and CDK 4/6 inhibitors have a synergistic anti-tumor effect when combined in human papillomavirus (HPV)-negative/PIK3CA-WT tumors. These findings provide a rationale for combining PI3Ki and CDK 4/6 inhibitors to enhance anti-tumor efficacy in HNSCC patients. Full article
(This article belongs to the Special Issue Frontiers in Oral Cancer—Basic and Clinical Sciences)
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12 pages, 1952 KiB  
Article
Nuclear Magnetic Resonance Metabolomics Biomarkers for Identifying High Risk Patients with Extranodal Extension in Oral Squamous Cell Carcinoma
by Cheng-Kun Tsai, Chien-Yu Lin, Chung-Jan Kang, Chun-Ta Liao, Wan-Ling Wang, Meng-Han Chiang, Tzu-Chen Yen and Gigin Lin
J. Clin. Med. 2020, 9(4), 951; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9040951 - 30 Mar 2020
Cited by 17 | Viewed by 2704
Abstract
Extranodal extension (ENE) is an independent adverse prognostic factor in oral squamous cell carcinoma (OSCC), and is difficult to identify preoperatively. We aimed to discover biomarkers for high risk patients with ENE. Tandem tissue, plasma, and urine samples of 110 patients with OSCC [...] Read more.
Extranodal extension (ENE) is an independent adverse prognostic factor in oral squamous cell carcinoma (OSCC), and is difficult to identify preoperatively. We aimed to discover biomarkers for high risk patients with ENE. Tandem tissue, plasma, and urine samples of 110 patients with OSCC were investigated through 600-MHz nuclear magnetic resonance (NMR) metabolomics analysis. We found that the levels of creatine, creatine phosphate, glycine, and tyramine in plasma significantly decreased in stage IV ENE positive OSCC compared with stage IV ENE negative OSCC. To understand the underlying mechanism behind the alteration of plasma metabolites, our tissue analysis revealed that the carnitine level significantly increased in tumors but significantly decreased in the adjacent normal tissue in advanced stage OSCC, in addition to decreased levels of alanine and pyruvate in tumor tissues. The global metabolomics analysis on tumor tissues also showed that stage IV tumors with an ENE positive status demonstrated higher levels of aspartate, butyrate, carnitine, glutamate, glutathione, glycine, glycolate, guanosine, and sucrose but lower levels of alanine, choline, glucose, isoleucine, lactate, leucine, myo-inositol, O-acetylcholine, oxypurinol, phenylalanine, pyruvate, succinate, tyrosine, valine, and xanthine than tumors with an ENE negative status. We concluded that metabolomics alterations in tumor tissues correspond to an increase in the tumor stage and are detectable in plasma samples. Metabolomic alterations of OSCC can serve as potential diagnostic markers and predictors of ENE in patients with stage IV OSCC. Full article
(This article belongs to the Special Issue Frontiers in Oral Cancer—Basic and Clinical Sciences)
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17 pages, 2839 KiB  
Article
Evaluation of Proinflammatory, NF-kappaB Dependent Cytokines: IL-1α, IL-6, IL-8, and TNF-α in Tissue Specimens and Saliva of Patients with Oral Squamous Cell Carcinoma and Oral Potentially Malignant Disorders
by Karolina Babiuch, Beata Kuśnierz-Cabala, Barbara Kęsek, Krzysztof Okoń, Dagmara Darczuk and Maria Chomyszyn-Gajewska
J. Clin. Med. 2020, 9(3), 867; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9030867 - 21 Mar 2020
Cited by 54 | Viewed by 4366
Abstract
Background: Oral squamous cell carcinoma (OSCC) is a life-threatening disease. It could be preceded by oral potentially malignant disorders (OPMDs). It was confirmed that chronic inflammation can promote carcinogenesis. Cytokines play a crucial role in this process. The aim of the study was [...] Read more.
Background: Oral squamous cell carcinoma (OSCC) is a life-threatening disease. It could be preceded by oral potentially malignant disorders (OPMDs). It was confirmed that chronic inflammation can promote carcinogenesis. Cytokines play a crucial role in this process. The aim of the study was to evaluate interleukin-1alpha (IL-1α), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α) in tissue specimens and saliva of patients with OSCC and OPMDs. Methods: Cytokines were evaluated in 60 tissue specimens of pathological lesions (OSCCs or OPMDs) and in 7 controls (normal oral mucosa, NOM) by immunohistochemistry and in saliva of 45 patients with OSCC or OPMDs and 9 controls (healthy volunteers) by enzyme-linked immunosorbent assays. Results: Immunohistochemical analysis revealed significantly higher expression of IL-8 in OSCC specimens and TNF-α in OSCCs and OPMDs with dysplasia as compared to NOM. Moreover, expression of TNF-α was significantly higher in oral leukoplakia and oral lichen planus without dysplasia, whereas expression of IL-8 only in oral leukoplakia without dysplasia in comparison with NOM. Salivary concentrations of all evaluated cytokines were significantly higher in patients with OSCC than in controls. Moreover, levels of IL-8 were significantly higher in saliva of patients with OPMDs with dysplasia as compared to controls and in OSCC patients as compared to patients with dysplastic lesions. There was also significant increase in salivary concentrations of IL-6, IL-8 and TNF-α in patients with OSCC as compared to patients with OPMDs without dysplasia. Conclusion: The study confirmed that proinflammatory, NF-kappaB dependent cytokines are involved in pathogenesis of OPMDs and OSCC. The most important biomarker of malignant transformation process within oral mucosa among all assessed cytokines seems to be IL-8. Further studies on a larger sample size are needed to corroborate these results. Full article
(This article belongs to the Special Issue Frontiers in Oral Cancer—Basic and Clinical Sciences)
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12 pages, 1824 KiB  
Article
Potential Salivary mRNA Biomarkers for Early Detection of Oral Cancer
by Su Young Oh, Sung-Min Kang, Soo Hyun Kang, Heon-Jin Lee, Tae-Geon Kwon, Jin-Wook Kim, Sung-Tak Lee, So-Young Choi and Su-Hyung Hong
J. Clin. Med. 2020, 9(1), 243; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9010243 - 16 Jan 2020
Cited by 31 | Viewed by 4722
Abstract
We evaluated potential biomarkers in human whole saliva for the early diagnosis of oral squamous cell carcinoma (OSCC). We selected 30 candidate genes with relevance to cancer from recent reports in PubMed. Saliva samples were obtained from 34 non-tumor control and 33 OSCC [...] Read more.
We evaluated potential biomarkers in human whole saliva for the early diagnosis of oral squamous cell carcinoma (OSCC). We selected 30 candidate genes with relevance to cancer from recent reports in PubMed. Saliva samples were obtained from 34 non-tumor control and 33 OSCC patients. Real-time PCR was performed, and mRNA levels were compared. Normalized mRNA levels of six genes (NGFI-A binding protein 2 (NAB2), cytochrome P450, family 27, subfamily A, polypeptide 1 (CYP27A1), nuclear pore complex interacting protein family, member B4 (NPIPB4), monoamine oxidase B (MAOB), sialic acid acetyltransferase (SIAE), and collagen, type III, alpha 1 (COL3A1)) were significantly lower in saliva of OSCC patients. Receiver operating characteristics (ROC) analysis was used to individually evaluate the predictive power of the potential biomarkers for OSCC diagnosis. The area under the curve (AUC) values were evaluated for the OSCC vs. non-tumor groups via univariate ROC analyses, as well as multivariate ROC analyses of combinations of multiple potential biomarkers. The combination of CYP27A1 + SIAE showed a favorable AUC value of 0.84. When we divided saliva samples into two groups according to age using a 60-year cut-off, with OSCC patients and controls evaluated together, the AUC of MAOB–NAB2 was more predictive of OSCC in the under-60 group (AUC, 0.91; sensitivity, 0.92; and specificity, 0.86) than any other gene combination. These results are expected to aid the early diagnosis of OSCC, especially in patients under 60 years of age. While more studies with larger numbers of patients are necessary, our result suggest that salivary mRNA would be a potent biomarker for early OSCC diagnosis. Full article
(This article belongs to the Special Issue Frontiers in Oral Cancer—Basic and Clinical Sciences)
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12 pages, 2026 KiB  
Article
Non-SMC Condensin I Complex Subunit H (NCAPH) Is Associated with Lymphangiogenesis and Drug Resistance in Oral Squamous Cell Carcinoma
by Hiroyuki Shimomura, Tomonori Sasahira, Chie Nakashima, Miyako Kurihara-Shimomura and Tadaaki Kirita
J. Clin. Med. 2020, 9(1), 72; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9010072 - 27 Dec 2019
Cited by 15 | Viewed by 2368
Abstract
Background: Head and neck cancer, including oral squamous cell carcinoma (OSCC), is the sixth most common malignancy. OSCC has strong invasive ability, and its malignant potential is closely associated with local expansion and lymph node metastasis. Furthermore, local or nodal recurrence worsens OSCC [...] Read more.
Background: Head and neck cancer, including oral squamous cell carcinoma (OSCC), is the sixth most common malignancy. OSCC has strong invasive ability, and its malignant potential is closely associated with local expansion and lymph node metastasis. Furthermore, local or nodal recurrence worsens OSCC prognosis. In our previous cDNA microarray analysis, non-structural maintenance of chromosome (SMC) condensin I complex subunit H (NCAPH) was identified as an upregulated gene in recurrent OSCC. Although NCAPH has several functions in tumors, its role in OSCC is unknown. Methods: In this study, we examined NCAPH expression in OSCC and performed a functional analysis of human OSCC cells. Results: NCAPH expression was higher in OSCC than in normal oral mucosa. In immunohistochemistry using 142 OSCC specimens, the immunostaining of NCAPH was strongly associated with nodal metastasis and lymphatic infiltration. In multivariate analysis using the Cox proportional hazards model, NCAPH expression was an independent poor prognostic indicator for OSCC. Moreover, NCAPH promoted the migration and adhesion of endothelial cells to OSCC cells and promoted the resistance to platinum anticancer drugs. Conclusions: Our present findings suggest that NCAPH is a novel diagnostic and therapeutic target in OSCC. Full article
(This article belongs to the Special Issue Frontiers in Oral Cancer—Basic and Clinical Sciences)
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15 pages, 1850 KiB  
Article
13-gene DNA Methylation Analysis from Oral Brushing: A Promising Non Invasive Tool in the Follow-up of Oral Cancer Patients
by Davide B. Gissi, Achille Tarsitano, Andrea Gabusi, Roberto Rossi, Giuseppe Attardo, Jacopo Lenzi, Claudio Marchetti, Lucio Montebugnoli, Maria P. Foschini and Luca Morandi
J. Clin. Med. 2019, 8(12), 2107; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8122107 - 02 Dec 2019
Cited by 12 | Viewed by 2732
Abstract
Background: This study aimed to evaluate the prognostic value of a non-invasive sampling procedure based on 13-gene DNA methylation analysis in the follow-up of patients previously treated for oral squamous cell carcinoma (OSCC). Methods: The study population included 49 consecutive patients treated for [...] Read more.
Background: This study aimed to evaluate the prognostic value of a non-invasive sampling procedure based on 13-gene DNA methylation analysis in the follow-up of patients previously treated for oral squamous cell carcinoma (OSCC). Methods: The study population included 49 consecutive patients treated for OSCC. Oral brushing sample collection was performed at two different times: before any cancer treatment in the tumor mass and during patient follow-up almost 6 months after OSCC treatment, within the regenerative area after OSCC resection. Each sample was considered positive or negative in relation to a predefined cut-off value. Results: Before any cancer treatment, 47/49 specimens exceeded the score and were considered as positive. Six months after OSCC resection, 16/49 specimens also had positive scores in the samples collected from the regenerative area. During the follow-up period, 7/49 patients developed locoregional relapse: 6/7 patients had a positive score in the regenerative area after OSCC resection. The presence of a positive score after oral cancer treatment was the most powerful variable related to the appearance of locoregional relapse. Conclusion: 13-gene DNA methylation analysis by oral brushing may have a clinical application as a prognostic non-invasive tool in the follow-up of patients surgically treated for OSCC. Full article
(This article belongs to the Special Issue Frontiers in Oral Cancer—Basic and Clinical Sciences)
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18 pages, 2600 KiB  
Article
Comprehensive Genomic Review of TCGA Head and Neck Squamous Cell Carcinomas (HNSCC)
by Mario Pérez Sayáns, Cintia Micaela Chamorro Petronacci, Alejandro Ismael Lorenzo Pouso, Elena Padín Iruegas, Andrés Blanco Carrión, José Manuel Suárez Peñaranda and Abel García García
J. Clin. Med. 2019, 8(11), 1896; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm8111896 - 07 Nov 2019
Cited by 46 | Viewed by 4743
Abstract
The aim of this present study was to comprehensively describe somatic DNA alterations and transcriptional alterations in the last extension of the HNSCC subsets in TCGA, encompassing a total of 528 tumours. In order to achieve this goal, transcriptional analysis, functional enrichment assays, [...] Read more.
The aim of this present study was to comprehensively describe somatic DNA alterations and transcriptional alterations in the last extension of the HNSCC subsets in TCGA, encompassing a total of 528 tumours. In order to achieve this goal, transcriptional analysis, functional enrichment assays, survival analysis, somatic copy number alteration analysis and somatic alteration analysis were carried out. A total of 3491 deregulated genes were found in HNSCC patients, and the functional analysis carried out determined that tissue development and cell differentiation were the most relevant signalling pathways in upregulated and downregulated genes, respectively. Somatic copy number alteration analysis showed a “top five” altered HNSCC genes: CDKN2A (deleted in 32.03% of patients), CDKN2B (deleted in 28.34% of patients), PPFIA1 (amplified in 26.02% of patients), FADD (amplified in 25.63% of patients) and ANO1 (amplified in 25.44% of patients). Somatic mutations analysis revealed TP53 mutation in 72% of the tumour samples followed by TTN (39%), FAT1 (23%) and MUC16 (19%). Another interesting result is the mutual exclusivity pattern that was discovered between the TP53 and PIK3CA mutations, and the co-occurrence of CDKN2A with the TP53 and FAT1 alterations. On analysis to relate differential expression genes and somatic copy number alterations, some genes were overexpressed and amplified, for example, FOXL2, but other deleted genes also showed overexpression, such as CDKN2A. Survival analysis revealed that overexpression of some oncogenes, such as EGFR, CDK6 or CDK4 were associated with poorer prognosis tumours. These new findings help us to develop new therapies and programs for the prevention of HNSCC. Full article
(This article belongs to the Special Issue Frontiers in Oral Cancer—Basic and Clinical Sciences)
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Review

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16 pages, 868 KiB  
Review
Organoids in Translational Oncology
by Marco Tatullo, Benedetta Marrelli, Caterina Benincasa, Elisabetta Aiello, Irina Makeeva, Barbara Zavan, Andrea Ballini, Danila De Vito and Gianrico Spagnuolo
J. Clin. Med. 2020, 9(9), 2774; https://0-doi-org.brum.beds.ac.uk/10.3390/jcm9092774 - 27 Aug 2020
Cited by 18 | Viewed by 3584
Abstract
Translational medicine aims to translate the most promising preclinical research into clinical practice. Oncology is a continuously growing medical field: the scientific research on cancer biology is currently based on in vitro experiments, carried out on tissue culture plates (TCPs) and other 2D [...] Read more.
Translational medicine aims to translate the most promising preclinical research into clinical practice. Oncology is a continuously growing medical field: the scientific research on cancer biology is currently based on in vitro experiments, carried out on tissue culture plates (TCPs) and other 2D samples. In this context, 3D printing has greatly improved the biofabrication of new biological matrices that mimic the extracellular environments, which may characterize healthy from cancerous tissues. Organoids have recently been described in several reports on scientific literature. The term that better describes such organoids-based tumoral tissues is “tumoroids”. Tumoroids are substantially “tumor-like organoids”, typically deriving from primary tumors harvested from patients. This topical review aims to give an update on organoids applied in translational medicine, paying specific attention to their use in the investigation of the main molecular mechanisms of cancer onset and growth, and on the most impacting strategies for effective targeted therapies. Full article
(This article belongs to the Special Issue Frontiers in Oral Cancer—Basic and Clinical Sciences)
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