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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 (20 September 2018) | Viewed by 76489

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Prof. Dr. Lorenzo Lo Muzio

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Direttore della Sezione di Medicina Sperimentale del Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Foggia, Foggia, Italy
Interests: oral cancer; cancer stem cell; biomarkers; protein function; protein bioinformatics; protein–protein interactions; structure bioinformatics; cancer pharmaco-omics modelling; biomarker discovery; precision oncology; chemoinformatics; drug discovery informatics; virtual screening
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Dear Colleagues,

Oral squamous cell carcinoma (OSCC) is the eight most common cancers worldwide, with an incidence that varies from 3–4% in North America and Europe, to 8–10% in Southwest Asia. Tobacco smoking, alcohol consumption and high-risk human papillomaviruses (HPV) infections are the most important risk factors for OSCC. Prognosis in OSCC is largely influenced by the stage at diagnosis. The most important prognostic factor is the involvement of lymph nodes, that decreases the survival rate by 50%. Furthermore, recurrences and distant metastases are associated with poor prognoses. Surgery is the standard treatment for OSCC, often followed by postoperative radiotherapy. Unfortunately, the survival rates have not significantly improved over the last decades, because of the high rate of recurrences and of advanced stages at presentation. The improved understanding of the mechanisms involved in cancer development may lead to the identification of new potential therapeutic targets, allowing the application of novel strategies to the clinical treatment of OSCC. The available conventional approaches in the treatment of advanced or recurrent/metastatic OSCC seems to have been reached a plateau during the past decades. Therefore, a wide spectrum of novel therapeutic agents is currently being tested in OSCC, with the aim to selectively target molecular signaling pathways or investigating immunotherapy and gene therapy strategies.

In the Special Issue on “Therapeutic and Oral Cancer”, we invite front-line researchers and investigators to submit both original research and review articles regarding the following potential topics, but not limited to:

Surgical Therapy of oral cancer;
Radiation Therapy of oral cancer;
Chemotherapy of oral cancer;
Targeted therapy of oral cancer (i.e., Receptor tyrosine kynases antibodies, Tyrosine kinase inhibitors, Multi-kinase inhibition, others);
Immunotherapy of oral cancer;
Gene therapy of oral cancer;
Oral cancer Prognosis;
Natural substances in the therapy of oral cancer (ie. Plants derivates, others)
Novel approach and proof of priciple in oral cancer therapy;
Related quality of life after oral canacer treatment;

Prof. Lorenzo Lo Muzio
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

oral cancer
squamous cell carcinoma
surgery
radiation therapy
chemotherapy
immunotherapy
gene therapy
targeted therapy
quality of life

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Related Special Issues

Oral Cancer—Diagnosis and Therapeutics 2020 in International Journal of Molecular Sciences (18 articles)
Oral Cancer—Etiopathogenesis and New Mechanisms of Oral Cancerogenesis in International Journal of Molecular Sciences (24 articles)

Published Papers (11 papers)

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Research

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20 pages, 4708 KiB

Open AccessArticle

Transfection of T-Box Transcription Factor BRACHYURY and SOX2 Synergistically Promote Self-Renewal and Invasive Phenotype in Oral Cancer Cells

by Naonari Akimoto, Kodai Nakamura, Hiroshi Hijioka, Kenichi Kume, Yoshiaki Matsumura and Tsuyoshi Sugiura

Int. J. Mol. Sci. 2018, 19(11), 3620; https://doi.org/10.3390/ijms19113620 - 16 Nov 2018

Cited by 11 | Viewed by 3958

Abstract

Recent studies suggest that epithelial–mesenchymal transition (EMT) correlates with cancer metastasis. In addition, there is growing evidence of the association of EMT with cancer stem cells (CSCs). Recently, we showed that the T-box transcription factor BRACHYURY could be a strong regulator of EMT and the CSC phenotype, which were effectively suppressed by a BRACHYURY knockdown in an adenoid cystic carcinoma cell line. In this study, we further tested whether BRACHYURY is a regulator of cancer stemness by means of forced expression of BRACHYURY in oral cancer cell lines. BRACHYURY, SOX2, or both were stably transfected into oral carcinoma cell lines. We analysed these transfectants with respect to self-renewal phenotypes using a sphere-formation assay, and we assessed the expression levels of EMT markers and stem cell markers using real-time reverse transcription-polymerase chain reaction (RT-PCR). Cell migration and invasiveness in vitro were evaluated using a wound healing assay and a tumour cell dissemination assay, respectively. Forced expression of BRACHYURY or SOX2 slightly increased expression of EMT and stem cell markers and the self-renewal phenotype. The expression levels, however, were much lower compared to those of cancer stem cell-like cells. Forced co-expression of BRACHYURY and SOX2 strongly upregulated EMT and stem cell markers and the self-renewal phenotype. Cell migration and invasiveness in vitro were also remarkably enhanced. These synergistic effects increased expression levels of FIBRONECTIN, SNAIL, SLUG, ZEB1, and TGF-β2. In particular, the effects on FIBRONECTIN and TGF-β2 were significant. We found that BRACHYURY and SOX2 synergistically promote cancer stemness in oral cancer cells. This finding points to the importance of gene or protein networks associated with BRACHYURY and SOX2 in the development and maintenance of the CSC phenotype. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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13 pages, 5279 KiB

Open AccessArticle

Lactate Transporter Monocarboxylate Transporter 4 Induces Bone Pain in Head and Neck Squamous Cell Carcinoma

by Kazuaki Hasegawa, Tatsuo Okui, Tsuyoshi Shimo, Soichiro Ibaragi, Hotaka Kawai, Shoji Ryumon, Koji Kishimoto, Yuka Okusha, Nur Mohammad Monsur Hassan and Akira Sasaki

Int. J. Mol. Sci. 2018, 19(11), 3317; https://doi.org/10.3390/ijms19113317 - 25 Oct 2018

Cited by 6 | Viewed by 3676

Abstract

Head and neck squamous cell carcinoma (HNSCC) poses a significant challenge clinically, as it can invade facial bones and cause bone pain that is undertreated and poorly understood. Here we studied HNSCC bone pain (HNSCC-BP) in an intratibial mouse xenograft model that uses a human HNSCC cell line (SAS cells). These mice develop HNSCC-BP associated with an upregulation of phosphorylated ERK1/2 (pERK1/2), which is a molecular indicator of neuron excitation in the dorsal root ganglia (DRGs) of sensory nerve cell bodies. Our experiments demonstrated that the inhibition of monocarboxylate transporter 4 (MCT4) by short hairpin (shRNA) transduction suppressed the HNSCC-BP, the lactate level in bone marrow, and the pERK1/2 expression in DRG. The sensory nerves also expressed increased levels of the acid-sensing receptor TRPV1. DRG neurons co-cultured with SAS cells showed increased neurite outgrowth, and were inhibited by MCT4 silencing with shRNA. Collectively, our results show that HNSCC induced an acidic bone microenvironment that evokes HNSCC-BP via MCT4 expression. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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15 pages, 2776 KiB

Open AccessArticle

The Multifarious Functions of Pyruvate Kinase M2 in Oral Cancer Cells

by Miyako Kurihara-Shimomura, Tomonori Sasahira, Chie Nakashima, Hiroki Kuniyasu, Hiroyuki Shimomura and Tadaaki Kirita

Int. J. Mol. Sci. 2018, 19(10), 2907; https://doi.org/10.3390/ijms19102907 - 25 Sep 2018

Cited by 33 | Viewed by 5120

Abstract

Head and neck cancers, including oral squamous cell carcinoma (OSCC), are the sixth most common malignancies worldwide. OSCC frequently leads to oral dysfunction, which worsens a patient’s quality of life. Moreover, its prognosis remains poor. Unlike normal cells, tumor cells preferentially metabolize glucose by aerobic glycolysis. Pyruvate kinase (PK) catalyzes the final step in glycolysis, and the transition from PKM1 to PKM2 is observed in many cancer cells. However, little is known about PKM expression and function in OSCC. In this study, we investigated the expression of PKM in OSCC specimens and performed a functional analysis of human OSCC cells. We found that the PKM2/PKM1 ratio was higher in OSCC cells than in adjacent normal mucosal cells and in samples obtained from dysplasia patients. Furthermore, PKM2 expression was strongly correlated with OSCC tumor progression on immunohistochemistry. PKM2 expression was higher during cell growth, invasion, and apoptosis in HSC3 cells, which show a high energy flow and whose metabolism depends on aerobic glycolysis and oxidative phosphorylation. PKM2 expression was also associated with the production of reactive oxygen species (ROS) and integration of glutamine into lactate. Our results suggested that PKM2 has a variety of tumor progressive functions in OSCC cells. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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15 pages, 3335 KiB

Open AccessArticle

Aspirin is Involved in the Cell Cycle Arrest, Apoptosis, Cell Migration, and Invasion of Oral Squamous Cell Carcinoma

by Xiaoqi Zhang, Hao Feng, Ziyu Li, Jie Guo and Minqi Li

Int. J. Mol. Sci. 2018, 19(7), 2029; https://doi.org/10.3390/ijms19072029 - 12 Jul 2018

Cited by 35 | Viewed by 4786

Abstract

Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide. In China, its 5-year survival rate is roughly 50%, owing to acquired chemotherapeutic resistance and metastasis of the disease. Accumulating evidence demonstrates that aspirin (ASA) acts as a preventive or therapeutic agent in multiple cancers; however, anti-tumor activities induced by aspirin are unclear in OSCC. To investigate the possible role of aspirin in OSCC development, we first employed bioinformatics to analyze the anti-OSCC effects of aspirin. We performed a genetic oncology (GO) enrichment analysis using the Database for Annotation, Visualization, and Integrated Discovery (DAVID), and the protein–protein interaction (PPI) network analysis by Cytoscape for differentially expressed genes (DEGs). We also evaluated the potential effects of aspirin on cell proliferation, invasion, migration, and apoptosis in two well-characterized OSCC cell lines (TCA8113 and CAL27). The bioinformatic results revealed that aspirin could inhibit proliferation by blocking the cell cycle, and could reduce migration and invasion via the PI3K-Akt and focal adhesion pathways. We found that ASA could downregulate the OSCC cell proliferation colony formation, invasion, and migration, as well as upregulate apoptosis. Furthermore, we found that ASA suppressed the activation of the focal adhesion kinase (FAK) and the phosphorylation of Akt, NF-κB, and STAT3. Overall, our data suggested that ASA may be developed as a chemopreventive agent to effectively treat OSCC. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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23 pages, 4664 KiB

Open AccessArticle

Nerve Growth Factor (NGF)—Receptor Survival Axis in Head and Neck Squamous Cell Carcinoma

by József Dudás, Wolfgang Dietl, Angela Romani, Susanne Reinold, Rudolf Glueckert, Anneliese Schrott-Fischer, Daniel Dejaco, Lejo Johnson Chacko, Raphaela Tuertscher, Volker Hans Schartinger and Herbert Riechelmann

Int. J. Mol. Sci. 2018, 19(6), 1771; https://doi.org/10.3390/ijms19061771 - 14 Jun 2018

Cited by 24 | Viewed by 5077

Abstract

Neurotrophins and their receptors might regulate cell survival in head and neck squamous cell carcinoma (HNSCC). mRNA expression of nerve growth factor (NGF) and protein synthesis of high (NTRK1) and low affinity neurotrophin (p75 neurotrophin receptor; NTR) receptors were investigated in normal oral mucosa and in HNSCC. HNSCC cell lines were treated with mitomycin C (MMC) and cell survival was investigated. Normal and malignant epithelial cells expressed NGF mRNA. NTRK1 was upregulated in 80% of HNSCC tissue, and 50% of HNSCC samples were p75NTR positive. Interestingly, in HNSCC tissue: NTRK1 and p75NTR immunohistochemical reactions were mutually exclusive. Detroit 562 cell line contained only p75NTR, UPCI-SCC090 cells synthesized NTRK1 but not p75NTR and SCC-25 culture had p75NTR and NTRK1 in different cells. NGF (100 ng/mL) significantly improved (1.4-fold) the survival of cultured UPCI-SCC090 cells after MMC-induced cell cycle arrest, while Detroit 562 cells with high levels of p75NTR did not even get arrested by single short MMC treatment. p75NTR in HNSCC might be related with NGF-independent therapy resistance, while NTRK1 might transduce a survival signal of NGF and contribute in this way to improved tumor cell survival after cell cycle arrest. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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17 pages, 18756 KiB

Open AccessArticle

Photodynamic Effect of Methylene Blue and Low Level Laser Radiation in Head and Neck Squamous Cell Carcinoma Cell Lines

by Barbara Kofler, Angela Romani, Christian Pritz, Teresa Bernadette Steinbichler, Volker Hans Schartinger, Herbert Riechelmann and Jozsef Dudas

Int. J. Mol. Sci. 2018, 19(4), 1107; https://doi.org/10.3390/ijms19041107 - 7 Apr 2018

Cited by 56 | Viewed by 7463

Abstract

Photodynamic therapy (PDT) is suggested to have an impact on the treatment of early stage head and neck cancers (HNSCC). We investigated the effect of PDT with methylene blue (MB) and a diode laser (660 nm) as the laser source on HNSCC cell lines as an in vitro model of surface oral squamous cell carcinoma. Cell-cultures were exposed to 160 µM MB for 4 min and to laser light for 8 min. Viability was proven via cell viability assay and clonogenic survival via clone counting assay. The combination of MB and diode laser evidenced high efficient loss of cell viability by 5% of the control, while treatment with the same concentration of MB for 4 min alone showed a viability of 46% of the control. In both SCC-25 and Detroit 562 HNSCC cells, MB combined with the laser allowed a significant abrogation of clonogenic growth (p < 0.01), especially in the case of Detroit 562 cells less than 1% of the suspension plated cells were able to grow tumor cell nests. Multiresistant (Detroit 562) HNSCC cells expressing cancer stem cell markers are sensitive to MB/red laser combined PDT. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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3983 KiB

Open AccessArticle

Midkine and NANOG Have Similar Immunohistochemical Expression Patterns and Contribute Equally to an Adverse Prognosis of Oral Squamous Cell Carcinoma

by Hyun-Min Kim, Young-Hoon Kang, June-Ho Byun, Si-Jung Jang, Gyu-Jin Rho, Jong-Sil Lee and Bong-Wook Park

Int. J. Mol. Sci. 2017, 18(11), 2339; https://doi.org/10.3390/ijms18112339 - 6 Nov 2017

Cited by 17 | Viewed by 4204

Abstract

To increase the overall survival rate and obtain a better prognosis for oral squamous cell carcinoma (OSCC) patients, the detection of more effective and reliable tumor prognostic markers is needed. This study is focused on the analysis of correlation between the clinicopathological features of OSCCs and the immunohistochemical (IHC) expression patterns of MIDKINE (MK) and NANOG. Sixty-two primary OSCC patients were selected and their pretreatment biopsy specimens were immunohistochemically analyzed for the MK and NANOG proteins. The IHC expression patterns, clinicopathological features, and overall survival rates were assessed to identify any correlations. MK and NANOG showed significantly similar IHC expression patterns: both demonstrated enhanced expression in histologically high-grade and clinically late-stage OSCCs. Weak or negative expression of MK and NANOG was correlated with negative neck node metastasis. Clinicopathologically, late tumor stage, neck node metastasis, high-grade tumor, and palliative treatment groups showed significantly lower overall survival rates. The enhanced expression of MK and NANOG was associated with lower overall survival rates. In particular, enhanced co-detection of MK and NANOG showed significant correlation with poor prognosis. In conclusion, enhanced IHC expression patterns of MK and NANOG in OSCC patients was significantly associated with lower overall survival rates and unfavorable clinicopathological features. These results demonstrate that analysis of IHC expression patterns of MK and NANOG in pretreatment biopsy specimens during the work-up period can provide a more definitive prognosis prediction for each OSCC patient that can help clinicians to develop a more precise individual treatment modality. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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Review

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21 pages, 667 KiB

Open AccessReview

Hallmarks of Cancer-Related Newly Prognostic Factors of Oral Squamous Cell Carcinoma

by Tomonori Sasahira and Tadaaki Kirita

Int. J. Mol. Sci. 2018, 19(8), 2413; https://doi.org/10.3390/ijms19082413 - 16 Aug 2018

Cited by 187 | Viewed by 16497

Abstract

Head and neck cancer, including oral squamous cell carcinoma (OSCC), is the sixth leading malignancy worldwide. OSCC is an aggressive tumor and its prognosis has exhibited little improvement in the last three decades. Comprehensive elucidation of OSCC’s molecular mechanism is imperative for early detection and treatment, improving patient survival. Based on broadly accepted notions, OSCC arises from multiple genetic alterations caused by chronic exposure to carcinogens. In 2011, research revealed 10 key alterations fundamental to cancer cell development: sustaining proliferative signaling, evading growth suppressors, avoiding immune destruction, activating invasion and metastasis, tumor-promoting inflammation, enabling replicative immortality, inducing angiogenesis, genome instability and mutation, resisting cell death, and deregulating energetics. This review describes molecular pathological findings on conventional and novel hallmarks of OSCC prognostic factors. In addition, the review summarizes the functions and roles of several molecules as novel OSCC prognosticators. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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15 pages, 571 KiB

Open AccessReview

Liquid Biopsy in Oral Cancer

by Fatima Lousada-Fernandez, Oscar Rapado-Gonzalez, Jose-Luis Lopez-Cedrun, Rafael Lopez-Lopez, Laura Muinelo-Romay and Maria Mercedes Suarez-Cunqueiro

Int. J. Mol. Sci. 2018, 19(6), 1704; https://doi.org/10.3390/ijms19061704 - 8 Jun 2018

Cited by 82 | Viewed by 10996

Abstract

Oral cancer is one of the most prevalent forms of cancer worldwide. Carcinogenesis is a complex process, in which heterogeneity plays an important role in the development and progression of the disease. This review provides an overview of the current biological and clinical significance of circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), and exosomes for diagnosis and prognosis of oral cancer. We highlight the importance of liquid biopsy—using blood and saliva—which represents a potential alternative to solid biopsy for diagnosis and prognosis. Moreover, liquid biomarkers allow for the real-time monitoring of tumour evolution and therapeutic responses, initiating the era of personalized medicine. However, in oral cancer, the impact of liquid biopsies in clinical settings is still limited, requiring further studies to discover the best scenario for its clinical use. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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20 pages, 1231 KiB

Open AccessReview

by Samadarani B. S. M. Siriwardena, Takaaki Tsunematsu, Guangying Qi, Naozumi Ishimaru and Yasusei Kudo

Int. J. Mol. Sci. 2018, 19(5), 1462; https://doi.org/10.3390/ijms19051462 - 14 May 2018

Cited by 44 | Viewed by 5763

Abstract

It is well recognized that the presence of cervical lymph node metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC). In solid epithelial cancer, the first step during the process of metastasis is the invasion of cancer cells into the underlying stroma, breaching the basement membrane (BM)—the natural barrier between epithelium and the underlying extracellular matrix (ECM). The ability to invade and metastasize is a key hallmark of cancer progression, and the most complicated and least understood. These topics continue to be very active fields of cancer research. A number of processes, factors, and signaling pathways are involved in regulating invasion and metastasis. However, appropriate clinical trials for anti-cancer drugs targeting the invasion of OSCC are incomplete. In this review, we summarize the recent progress on invasion-related factors and emerging molecular determinants which can be used as potential for diagnostic and therapeutic targets in OSCC. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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24 pages, 30261 KiB

Open AccessReview

Survivin-Based Treatment Strategies for Squamous Cell Carcinoma

by Andrea Santarelli, Marco Mascitti, Lucio Lo Russo, Davide Sartini, Giuseppe Troiano, Monica Emanuelli and Lorenzo Lo Muzio

Int. J. Mol. Sci. 2018, 19(4), 971; https://doi.org/10.3390/ijms19040971 - 24 Mar 2018

Cited by 43 | Viewed by 7163

Abstract

Survivin, an anti-apoptotic molecule abundantly expressed in most human neoplasms, has been reported to contribute to cancer initiation and drug resistance in a wide variety of human tumors. Efficient downregulation of survivin can sensitize tumor cells to various therapeutic interventions, generating considerable efforts in its validation as a new target in cancer therapy. This review thoroughly analyzes up-to-date information on the potential of survivin as a therapeutic target for new anticancer treatments. The literature dealing with the therapeutic targeting of survivin will be reviewed, discussing specifically squamous cell carcinomas (SCCs), and with emphasis on the last clinical trials. This review gives insight into the recent developments undertaken in validating various treatment strategies that target survivin in SCCs and analyze the translational possibility, identifying those strategies that seem to be the closest to being incorporated into clinical practice. The most recent developments, such as dominant-negative survivin mutants, RNA interference, anti-sense oligonucleotides, small-molecule inhibitors, and peptide-based immunotherapy, seem to be helpful for effectively downregulating survivin expression and reducing tumor growth potential, increasing the apoptotic rate, and sensitizing tumor cells to chemo- and radiotherapy. However, selective and efficient targeting of survivin in clinical trials still poses a major challenge. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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