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Pathogenesis and Therapy of Oral Carcinogenesis, 2nd Edition
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Pathogenesis and Therapy of Oral Carcinogenesis, 2nd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (20 November 2024) | Viewed by 13206

Special Issue Editors

Dr. Marko Tarle

E-Mail Website
Guest Editor
1. Department of Maxillofacial Surgery, Dubrava University Hospital, 10 000 Zagreb, Croatia
2. School of Dental Medicine, University of Zagreb, 10 000 Zagreb, Croatia
Interests: oral cancer; head and neck cancer; cancer therapy; molecular biomarkers; maxillofacial surgery
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Ivica Lukšić

E-Mail Website
Guest Editor
1. Department of Maxillofacial Surgery, Dubrava University Hospital, 10 000 Zagreb, Croatia
2. School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia
Interests: head & neck surgery; plastic & reconstructive surgery; neck cancer; salivary gland tumor; oral cavity carcinoma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite the development of diagnostic and therapeutic strategies in recent decades, oral squamous cell carcinoma (OSCC) has a high morbidity and mortality (less than 50%), and represents a major challenge for scientists and clinicians. Although the oral cavity is readily accessible for clinical examination, in 2020, 377,713 people worldwide were diagnosed with lip and oral cancer, while 177,757 people died from it, with a trend toward increasing numbers of patients younger than 50 years of age. Preventive oral screening for high-risk patients and the detection, monitoring and treatment of oral potentially malignant disorders (OPMD) such as oral leukoplakia (OL) and oral erythroplakia (OE) are essential for the prevention of OSCC. New biomarkers for OPMD that indicate a high risk of malignant transformation need to be identified, and the approach to the treatment and follow-up of these patients needs to be modified, as does the development of drugs that reduce the progression of genetic changes in apparently healthy mucosa.

The shortcomings of histopathologic classification systems in predicting the malignant transformation of OPMD and the survival prognosis of patients with OSCC motivate us to explore the complex molecular pathways involved in the development of oral cavity cancer and its spread to regional lymph nodes and distant organs.

In this Special Issue, we encourage the publication of research and review articles addressing the various molecular mechanisms involved in the different steps of oral carcinogenesis that could serve as diagnostic biomarkers and therapeutic targets.

Dr. Marko Tarle
Prof. Dr. Ivica Lukšić
Guest Editors

Manuscript Submission Information

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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.

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Keywords

  • oral cancer
  • oral premalignant disorders
  • tumor microenvironment
  • molecular biomarkers
  • targeted therapy
  • oral tumorigenesis

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Related Special Issue

Published Papers (7 papers)

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Research

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24 pages, 547 KiB  
Article
Investigating the Link between STAT4 Genetic Variants, STAT4 Protein Concentrations, and Laryngeal Squamous Cell Carcinoma: A Comprehensive Analysis of Clinical Manifestations
by Enrika Pileckaite, Alvita Vilkeviciute, Loresa Kriauciuniene, Vykintas Liutkevicius and Rasa Liutkeviciene
Int. J. Mol. Sci. 2024, 25(18), 10180; https://doi.org/10.3390/ijms251810180 - 22 Sep 2024
Viewed by 3017
Abstract
According to recent research, inflammatory STAT4 and its protein impact may be important factors in developing cancerous diseases. Still unanalyzed is this effect in patients with laryngeal squamous cell carcinoma (LSCC). In the present study, we evaluated four single nucleotide variants (SNVs) of [...] Read more.
According to recent research, inflammatory STAT4 and its protein impact may be important factors in developing cancerous diseases. Still unanalyzed is this effect in patients with laryngeal squamous cell carcinoma (LSCC). In the present study, we evaluated four single nucleotide variants (SNVs) of STAT4 (rs10181656, rs7574865, rs7601754, and rs10168266) and STAT4 serum levels to determine their link between LSCC development and its clinical manifestations. A total of 632 men (324 LSCC patients and 338 healthy individuals) were involved in this study. The genotyping was carried out using real-time PCR. Additionally, we measured 80 study subjects’ (40 LSCC patients and 40 control subjects) STAT4 protein concentrations using an enzyme-linked immunosorbent assay (ELISA). In our study, the T allele of STAT4 rs7574865 significantly increases the likelihood of LSCC occurrence by 1.4-fold. Additionally, this SNV is associated with higher odds of early-stage disease, T1 size LSCC development, absence of metastasis to neck lymph nodes, and well-differentiated carcinoma. The G allele of rs10181656 is significantly associated with various clinical characteristics of LSCC, increasing the odds of early- and advanced-stage disease by 2.8-fold and 1.9-fold, respectively. Additionally, this allele is linked to an increased likelihood of developing tumors of different sizes and non-metastasized LSCC, as well as poorly differentiated carcinoma, highlighting its potential impact on the development and features of LSCC. Conclusion: The analysis of the STAT4 rs7574865 SNV revealed that the G allele is linked to a more favorable prognosis in LSCC. Additionally, it is hypothesized that the G allele of rs10181656 may be associated with the occurrence of LSCC but may not serve as a sensitive prognostic biomarker for distinguishing between disease stages, cell differentiation, or tumor size. Full article
(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis, 2nd Edition)
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14 pages, 3081 KiB  
Article
Differential Immune Checkpoint Protein Expression in HNSCC: The Role of HGF/MET Signaling
by Verena Boschert, Johannes Boenke, Ann-Kathrin Böhm, Jonas Teusch, Valentin Steinacker, Anton Straub and Stefan Hartmann
Int. J. Mol. Sci. 2024, 25(13), 7334; https://doi.org/10.3390/ijms25137334 - 4 Jul 2024
Viewed by 1117
Abstract
Although inhibitors targeting the PD1/PD-L1 immune checkpoint are showing comparably good outcomes, a significant percentage of head and neck squamous cell carcinoma (HNSCC) patients do not respond to treatment. Apart from using different treatment strategies, another possibility would be to target other immune [...] Read more.
Although inhibitors targeting the PD1/PD-L1 immune checkpoint are showing comparably good outcomes, a significant percentage of head and neck squamous cell carcinoma (HNSCC) patients do not respond to treatment. Apart from using different treatment strategies, another possibility would be to target other immune checkpoints operating in these non-responding tumors. To obtain an overview of which checkpoint ligands are expressed on HNSCC tumor cells and if these ligands are affected by HGF/MET signaling, we used mRNA sequencing and antibody-based techniques for identifying checkpoint ligands in six HNSCC tumor cell lines. Furthermore, we compared our results to mRNA sequencing data. From the checkpoint ligands we investigated, VISTA was expressed the highest at the RNA level and was also the most ubiquitously expressed. PD-L2 and B7-H3 were expressed comparably lower and were not present in all cell lines to the same extent. B7-H4, however, was only detectable in the Detroit 562 cell line. Concerning the effect of HGF on the ligand levels, PD-L2 expression was enhanced with HGF stimulation, whereas other checkpoint ligand levels decreased with stimulation. B7-H4 levels in the Detroit 562 cell line drastically decreased with HGF stimulation. This is of interest because both the checkpoint ligand and the growth factor are reported to be connected to epithelial–mesenchymal transition in the literature. Full article
(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis, 2nd Edition)
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17 pages, 5974 KiB  
Article
Development of an Ex Vivo Functional Assay for Prediction of Irradiation Related Toxicity in Healthy Oral Mucosa Tissue
by Katrin S. Pachler, Iris Lauwers, Nicole S. Verkaik, Marta Rovituso, Ernst van der Wal, Hetty Mast, Brend P. Jonker, Aniel Sewnaik, Jose A. Hardillo, Stijn Keereweer, Dominiek Monserez, Bernd Kremer, Sjors Koppes, Thierry P. P. van den Bosch, Gerda M. Verduijn, Steven Petit, Brita S. Sørensen, Dik C. van Gent and Marta E. Capala
Int. J. Mol. Sci. 2024, 25(13), 7157; https://doi.org/10.3390/ijms25137157 - 28 Jun 2024
Viewed by 999
Abstract
Radiotherapy in the head-and-neck area is one of the main curative treatment options. However, this comes at the cost of varying levels of normal tissue toxicity, affecting up to 80% of patients. Mucositis can cause pain, weight loss and treatment delays, leading to [...] Read more.
Radiotherapy in the head-and-neck area is one of the main curative treatment options. However, this comes at the cost of varying levels of normal tissue toxicity, affecting up to 80% of patients. Mucositis can cause pain, weight loss and treatment delays, leading to worse outcomes and a decreased quality of life. Therefore, there is an urgent need for an approach to predicting normal mucosal responses in patients prior to treatment. We here describe an assay to detect irradiation responses in healthy oral mucosa tissue. Mucosa specimens from the oral cavity were obtained after surgical resection, cut into thin slices, irradiated and cultured for three days. Seven samples were irradiated with X-ray, and three additional samples were irradiated with both X-ray and protons. Healthy oral mucosa tissue slices maintained normal morphology and viability for three days. We measured a dose-dependent response to X-ray irradiation and compared X-ray and proton irradiation in the same mucosa sample using standardized automated image analysis. Furthermore, increased levels of inflammation-inducing factors—major drivers of mucositis development—could be detected after irradiation. This model can be utilized for investigating mechanistic aspects of mucositis development and can be developed into an assay to predict radiation-induced toxicity in normal mucosa. Full article
(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis, 2nd Edition)
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23 pages, 6133 KiB  
Article
The Immune Checkpoint BTLA in Oral Cancer: Expression Analysis and Its Correlation to Other Immune Modulators
by Jutta Ries, Leah Trumet, Alina Hahn, Lina Kunater, Rainer Lutz, Carol Geppert, Marco Kesting and Manuel Weber
Int. J. Mol. Sci. 2024, 25(12), 6601; https://doi.org/10.3390/ijms25126601 - 15 Jun 2024
Viewed by 1203
Abstract
In oral squamous cell carcinoma (OSCC) tissues, an immunotolerant situation triggered by immune checkpoints (ICPs) can be observed. Immune checkpoint inhibitors (ICIs) against the PD1/PD-L axis are used with impressive success. However, the response rate is low and the development of acquired resistance [...] Read more.
In oral squamous cell carcinoma (OSCC) tissues, an immunotolerant situation triggered by immune checkpoints (ICPs) can be observed. Immune checkpoint inhibitors (ICIs) against the PD1/PD-L axis are used with impressive success. However, the response rate is low and the development of acquired resistance to ICI treatment can be observed. Therefore, new treatment strategies especially involving immunological combination therapies need to be developed. The novel negative immune checkpoint BTLA has been suggested as a potential biomarker and target for antibody-based immunotherapy. Moreover, improved response rates could be displayed for tumor patients when antibodies directed against BTLA were used in combination with anti-PD1/PD-L1 therapies. The aim of the study was to check whether the immune checkpoint BTLA is overexpressed in OSCC tissues compared to healthy oral mucosa (NOM) and could be a potential diagnostic biomarker and immunological target in OSCC. In addition, correlation analyses with the expression of other checkpoints should clarify more precisely whether combination therapies are potentially useful for the treatment of OSCC. A total of 207 tissue samples divided into 2 groups were included in the study. The test group comprised 102 tissue samples of OSCC. Oral mucosal tissue from 105 healthy volunteers (NOM) served as the control group. The expression of two isoforms of BTLA (BTLA-1/2), as well as PD1, PD-L1/2 and CD96 was analyzed by RT-qPCR. Additionally, BTLA and CD96 proteins were detected by IHC. Expression levels were compared between the two groups, the relative differences were calculated, and statistical relevance was determined. Furthermore, the expression rates of the immune checkpoints were correlated to each other. BTLA expression was significantly increased in OSCC compared to NOM (pBTLA_1 = 0.003; pBTLA_2 = 0.0001, pIHC = 0.003). The expression of PD1, its ligands PD-L1 and PD-L2, as well as CD96, were also significantly increased in OSCC (p ≤ 0.001). There was a strong positive correlation between BTLA expression and that of the other checkpoints (p < 0.001; ρ ≥ 0.5). BTLA is overexpressed in OSCC and appears to be a relevant local immune checkpoint in OSCC. Thus, antibodies directed against BTLA could be potential candidates for immunotherapies, especially in combination with ICI against the PD1/PD-L axis and CD96. Full article
(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis, 2nd Edition)
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11 pages, 1241 KiB  
Article
BIRC5 Gene Polymorphisms Are Associated with a Higher Stage of Local and Regional Disease in Oral and Oropharyngeal Squamous Cell Carcinomas
by Ivan Mumlek, Petar Ozretić, Maja Sabol, Matko Leović, Ljubica Glavaš-Obrovac, Dinko Leović and Vesna Musani
Int. J. Mol. Sci. 2023, 24(24), 17490; https://doi.org/10.3390/ijms242417490 - 14 Dec 2023
Cited by 2 | Viewed by 1446
Abstract
Oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC) are the most common types of cancers in the head and neck region (HNSCC). Despite very aggressive treatment modalities, the five-year survival rate has not changed for decades and is still around [...] Read more.
Oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC) are the most common types of cancers in the head and neck region (HNSCC). Despite very aggressive treatment modalities, the five-year survival rate has not changed for decades and is still around 60%. The search for potential specific biomarkers of aggressiveness or outcome indicators could be of great benefit in improving the treatment of these patients. One of the potential biomarkers is survivin, the protein product of the BIRC5 gene. In this study, we investigated the occurrence of BIRC5 gene polymorphisms in 48 patients with OSCC and OPSCC compared with healthy controls. A total of 18 polymorphisms were found, 11 of which occurred in HNSCC with a minor allele frequency (MAF) of more than 5%. Five polymorphisms (rs3764383, rs9904341, rs2071214, rs2239680, rs2661694) were significantly associated with tumor size, tumor stage, and advanced regional disease, but had no impact on survival. Full article
(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis, 2nd Edition)
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12 pages, 1967 KiB  
Article
Developing New Diagnostic Tools Based on SERS Analysis of Filtered Salivary Samples for Oral Cancer Detection
by Rareș-Mario Borșa, Valentin Toma, Anca Onaciu, Cristian-Silviu Moldovan, Radu Mărginean, Diana Cenariu, Gabriela-Fabiola Știufiuc, Cristian-Mihail Dinu, Simion Bran, Horia-Octavian Opriș, Sergiu Văcăraș, Florin Onișor-Gligor, Dorin Sentea, Mihaela-Felicia Băciuț, Cristina-Adela Iuga and Rareș-Ionuț Știufiuc
Int. J. Mol. Sci. 2023, 24(15), 12125; https://doi.org/10.3390/ijms241512125 - 28 Jul 2023
Cited by 4 | Viewed by 1860
Abstract
Cancer still represents one of the biggest challenges in current medical practice. Among different types of cancer, oral cancer has a huge impact on patients due to its great visibility, which is more likely to create social stigma and increased anxiety. New early [...] Read more.
Cancer still represents one of the biggest challenges in current medical practice. Among different types of cancer, oral cancer has a huge impact on patients due to its great visibility, which is more likely to create social stigma and increased anxiety. New early diagnose methods are still needed to improve treatment efficiency and patients’ life quality. Raman/SERS (Surface Enhanced Raman Spectroscopy) spectroscopy has a unique and powerful potential for detecting specific molecules that can become priceless biomarkers in different pathologies, such as oral cancer. In this study, a batch of saliva samples obtained from a group of 17 patients with oro-maxillofacial pathologies compared with saliva samples from 18 healthy donors using the aforementioned methods were evaluated. At the same time, opiorphin, potassium thiocyanate and uric acid were evaluated as potential specific biomarkers for oro-maxillofacial pathologies using multivariate analysis. A careful examination of SERS spectra collected on saliva samples showed that the spectra are dominated by the vibrational bands of opiorphin, potassium thiocyanate and uric acid. Given the fact that all these small molecules are found in very small amounts, we filtrated all the samples to get rid of large molecules and to improve our analysis. By using solid plasmonic substrates, we were able to gain information about molecular concentration and geometry of interaction. On the other hand, the multivariate analysis of the salivary spectra contributed to developing a new detection method for oral cancer. Full article
(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis, 2nd Edition)
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Review

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34 pages, 795 KiB  
Review
Onco-Ontogeny of Squamous Cell Cancer of the First Pharyngeal Arch Derivatives
by Daniel Sat-Muñoz, Luz-Ma.-Adriana Balderas-Peña, Eduardo Gómez-Sánchez, Brenda-Eugenia Martínez-Herrera, Benjamín Trujillo-Hernández, Luis-Aarón Quiroga-Morales, Mario Salazar-Páramo, Ingrid-Patricia Dávalos-Rodríguez, Carlos M. Nuño-Guzmán, Martha-Cecilia Velázquez-Flores, Miguel-Ricardo Ochoa-Plascencia, María-Ivette Muciño-Hernández, Mario-Alberto Isiordia-Espinoza, Mario-Alberto Mireles-Ramírez and Eduardo Hernández-Salazar
Int. J. Mol. Sci. 2024, 25(18), 9979; https://doi.org/10.3390/ijms25189979 - 16 Sep 2024
Viewed by 1146
Abstract
Head and neck squamous cell carcinoma (H&NSCC) is an anatomic, biological, and genetic complex disease. It involves more than 1000 genes implied in its oncogenesis; for this review, we limit our search and description to the genes implied in the onco-ontogeny of the [...] Read more.
Head and neck squamous cell carcinoma (H&NSCC) is an anatomic, biological, and genetic complex disease. It involves more than 1000 genes implied in its oncogenesis; for this review, we limit our search and description to the genes implied in the onco-ontogeny of the derivates from the first pharyngeal arch during embryo development. They can be grouped as transcription factors and signaling molecules (that act as growth factors that bind to receptors). Finally, we propose the term embryo-oncogenesis to refer to the activation, reactivation, and use of the genes involved in the embryo’s development during the oncogenesis or malignant tumor invasion and metastasis events as part of an onco-ontogenic inverse process. Full article
(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis, 2nd Edition)
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