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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (15 March 2022) | Viewed by 29861

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Prof. Dr. Jan Plzak

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Department of Otorhinolaryngology, Head and Neck Surgery, First Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
Interests: head and neck cancer; microenvironment; tumor epidemiology; predictive markers; anterior skull base; rhinology; thyroid surgery
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Dear Colleagues,

During the last 5 to 10 years, a wide range of information about head and neck cancers, both malignant and benign, has been published, bringing key prognostic and therapeutic improvements for patients. Recently, a more complex approach has been used for making therapeutic decisions, including otorhinolaryngological treatments and skull base surgery. However, the identification of more precise and reliable prognostic markers is necessary.

This Special Issue aims to present original basic, translational, or clinical research or review articles that focus on aspects of head and neck cancer treatment, including mechanisms of disease, translational medical research, biomaterials, therapies including biological therapies and immunotherapies, biomarkers, novel insights into treatment of recurrent and metastatic disease, as well as the personalization of treatment based on the molecular characteristics of individual tumors.

Prof. Dr. Jan Plzak
Guest Editor

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Keywords

Head and Neck Tumors
Microenvironment
Predictive Markers
Therapy

Published Papers (12 papers)

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Research

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17 pages, 3473 KiB

Open AccessArticle

Enhanced Cytotoxic Effects in Human Oral Squamous Cell Carcinoma Cells Treated with Combined Methyltransferase Inhibitors and Histone Deacetylase Inhibitors

by Ryosuke Ushio, Miki Hiroi, Ari Matsumoto, Kazumasa Mori, Nobuharu Yamamoto and Yoshihiro Ohmori

Biomedicines 2022, 10(4), 763; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10040763 - 24 Mar 2022

Cited by 3 | Viewed by 1827

Abstract

Combined treatment of human oral squamous cell carcinoma (OSCCs) with DNA methyltransferase inhibitors (DNMTis), histone methyltransferase inhibitors (HMTis), and histone deacetylase inhibitors (HDACis), and the molecular mechanisms underlying their anticancer effects, have not been fully elucidated. Herein, we investigated the cytotoxic effects of combined DNMTis (5-Aza-deoxycytidine: 5-Aza-dC, RG108), HMTis (3-deazaneplanocin A: DZNep), and HDACis (trichostatin A: TSA) treatment on human OSCC cells and explored their molecular mechanisms. Combined 5-Aza-dC, or RG108, and TSA treatment significantly decreased HSC-2 and Ca9-22 cell viability. Combinatorial DZNep and TSA treatment also decreased Ca9-22 cell viability. Although caspase 3/7 activation was not observed in HSC-2 cells following combined treatment, caspase activity was significantly increased in Ca9-22 cells treated with DZNep and TSA. Moreover, combined treatment with 5-Aza-dC, RG108, and TSA increased the proportion of HSC-2 and Ca9-22 cells in the S and G2/M phases. Meanwhile, increased phosphorylation of the histone variant H2A.X, a marker of double-stranded DNA breaks, was observed in both cells after combination treatment. Hence, the decreased viability induced by combined treatment with epigenomic inhibitors results from apoptosis and cell cycle arrest in S and G2/M phases. Thus, epigenomic therapy comprising combined low concentrations of DNMTi, HMTi, and HDACi is effective against OSCC. Full article

(This article belongs to the Special Issue Head and Neck Tumors)

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12 pages, 2666 KiB

Open AccessArticle

Gb3/cd77 Is a Predictive Marker and Promising Therapeutic Target for Head and Neck Cancer

by Lorena García-Hevia, Débora Muñoz-Guerra, Íñigo Casafont, Carmelo Morales-Angulo, Victor J. Ovejero, David Lobo and Mónica L. Fanarraga

Biomedicines 2022, 10(4), 732; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10040732 - 22 Mar 2022

Cited by 3 | Viewed by 2190

Abstract

Head and neck squamous cell carcinoma is the sixth leading cancer in the world. This cancer is difficult to treat and is characterized by recurrences that are often fatal. This cancer is generally removed surgically, but it often regrows from the edges of the lesion from where most recurrences reappear. In this study, we have investigated if the expression of GB3 in human cell lines, tissues from patient biopsies, and a murine animal model could be used as an early and determinant marker of HNC. We found that in all the investigated systems, this marker appears in neoplastic cells from the very early stages of their malignant transformation. Our conclusions support the hypothesis that GB3 is a reliable and independent target for HNC identification and selective delivery of treatments. Furthermore, we show that the level of expression of this marker correlates with the degree of malignancy of the tumor. These studies suggest that GB3 may provide the basis for the early identification and new targeted therapies for head and neck cancer. Full article

(This article belongs to the Special Issue Head and Neck Tumors)

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28 pages, 1106 KiB

Open AccessArticle

Inflammation Status and Body Composition Predict Two-Year Mortality of Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma under Provision of Recommended Energy Intake during Concurrent Chemoradiotherapy

by Yu-Ching Lin, Cheng-Hsu Wang, Hang Huong Ling, Yi-Ping Pan, Pei-Hung Chang, Wen-Chi Chou, Fang-Ping Chen and Kun-Yun Yeh

Biomedicines 2022, 10(2), 388; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020388 - 06 Feb 2022

Cited by 3 | Viewed by 1650

Abstract

Only few prospective cohort trials have evaluated the risk factors for the 2-year mortality rate between two patient subgroups with locally advanced head and neck squamous cell carcinoma (LAHNSCC): oral cavity cancer with adjuvant concurrent chemoradiotherapy (CCRT) (OCC) and non-oral cavity cancer with primary CCRT (NOCC), under the recommended calorie intake and investigated the interplay among calorie supply, nutrition–inflammation biomarkers (NIBs), and total body composition change (TBC), as assessed using dual-energy X-ray absorptiometry (DXA). Patients with LAHNSCC who consumed at least 25 kcal/kg/day during CCRT were prospectively recruited. Clinicopathological variables, blood NIBs, CCRT-related factors, and TBC data before and after treatment were collected. Factor analysis was performed to reduce the number of anthropometric and DXA-derived measurements. Cox proportional hazards models were used for analysis. We enrolled 123 patients with LAHNSCC (69 with OCC and 54 with NOCC). The mean daily calorie intake correlated with the treatment interval changes in total body muscle and fat. Patients consuming ≥30 kcal/kg/day had lower pretreatment levels but exhibited fewer treatment interval changes in anthropometric and DXA measurements than patients consuming <30 kcal/kg/day. In the multivariate analysis of the 2-year mortality rate, the prognostic influence of the recommended calorie intake could not be confirmed, but different risk factors (performance status, pretreatment platelet-to-lymphocyte ratio, and treatment interval body muscle changes in patients with OCC; age, pretreatment neutrophil-to-lymphocyte ratio, and body fat storage in patients with NOCC) showed independent effects. Therefore, the inflammation status and body composition, but not the recommended calorie supply, contribute to the 2-year mortality rate for patients with LAHNSCC receiving CCRT. Full article

(This article belongs to the Special Issue Head and Neck Tumors)

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14 pages, 4465 KiB

Open AccessArticle

Master Regulators of Epithelial-Mesenchymal Transition and WNT Signaling Pathways in Juvenile Nasopharyngeal Angiofibromas

by Naiade Calanca, Sara Martoreli Silveira Binato, Sabrina Daniela da Silva, Helena Paula Brentani, Luiz Ubirajara Sennes, Clóvis Antonio Lopes Pinto, Maria Aparecida Custódio Domingues, Carlos Eduardo Fonseca-Alves, Claudia Aparecida Rainho and Silvia Regina Rogatto

Biomedicines 2021, 9(9), 1258; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9091258 - 18 Sep 2021

Cited by 3 | Viewed by 2612

Abstract

Juvenile nasopharyngeal angiofibroma (JNA) is a rare fibrovascular benign tumor showing an invasive growth pattern and affecting mainly male adolescents. We investigated the role of epithelial–mesenchymal transition (EMT) and WNT signaling pathways in JNA. Gene expression profiles using nine JNA paired with four inferior nasal turbinate samples were interrogated using a customized 2.3K microarray platform containing genes mainly involved in EMT and WNT/PI3K pathways. The expression of selected genes (BCL2, CAV1, CD74, COL4A2, FZD7, ING1, LAMB1, and RAC2) and proteins (BCL2, CAV1, CD74, FZD7, RAF1, WNT5A, and WNT5B) was investigated by RT-qPCR (28 cases) and immunohistochemistry (40 cases), respectively. Among 104 differentially expressed genes, we found a significantly increased expression of COL4A2 and LAMB1 and a decreased expression of BCL2 and RAC2 by RT-qPCR. The immunohistochemistry analysis revealed a low expression of BCL2 and a negative to moderate expression of FZD7 in most samples, while increased CAV1 and RAF1 expression were detected. Moderate to strong CD74 protein expression was observed in endothelial and inflammatory cells. A significant number of JNAs (78%) presented reduced WNT5A and increased WNT5B expression. Overall, the transcript and protein profile indicated the involvement of EMT and WNT pathways in JNA. These candidates are promising druggable targets for treating JNA. Full article

(This article belongs to the Special Issue Head and Neck Tumors)

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16 pages, 1963 KiB

Open AccessArticle

High PD-L1 Expression on Tumor Cells Indicates Worse Overall Survival in Advanced Oral Squamous Cell Carcinomas of the Tongue and the Floor of the Mouth but Not in Other Oral Compartments

by Łukasz Jan Adamski, Anna Starzyńska, Paulina Adamska, Michał Kunc, Monika Sakowicz-Burkiewicz, Giulia Marvaso, Daniela Alterio, Aleksandra Korwat, Barbara Alicja Jereczek-Fossa and Rafał Pęksa

Biomedicines 2021, 9(9), 1132; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9091132 - 01 Sep 2021

Cited by 8 | Viewed by 2198

Abstract

The markers of the tumor microenvironment (TME) are promising prognostic and predictive factors in oral squamous cell carcinoma (OSCC). The current study aims to analyze the immunohistochemical expression of programmed cell death-ligand 1 (PD-L1) and interleukin-33 (IL-33) in a cohort of 95 chemonaïve OSCCs. PD-L1 and IL-33 were assessed separately in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs). High PD-L1 expression in TILs was associated with better overall survival (OS) in univariate analysis. Tumors localized in the floor of the oral cavity and tongue tended to have a lower percentage of PD-L1-positive TCs when compared to other locations. PD-L1 expression on TCs had no prognostic significance when the whole cohort was analyzed. However, along with the T descriptor (TNM 8^th), it was included in the multivariable model predicting death in carcinomas of the floor of the oral cavity and tongue (HR = 2.51, 95% CI = 1.97–5.28). In other locations, only nodal status was identified as an independent prognostic factor in multivariate analysis (HR = 0.24, 95% CI = 0.08–0.70). Expression of IL-33 had no impact on survival, but it was differently expressed in various locations. In conclusion, the prognostic significance of PD-L1 in oral cancer depends on the tumor site and type of cell expressing immune checkpoint receptor (TCs vs. TILs). Full article

(This article belongs to the Special Issue Head and Neck Tumors)

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13 pages, 747 KiB

Open AccessArticle

Genetic Variants in Patients with Multiple Head and Neck Paragangliomas: Dilemma in Management

by Anasuya Guha, Ales Vicha, Tomas Zelinka, Zdenek Musil and Martin Chovanec

Biomedicines 2021, 9(6), 626; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060626 - 31 May 2021

Cited by 7 | Viewed by 4626

Abstract

Multiple head and neck paragangliomas (HNPGLs) are neuroendocrine tumors of a mostly benign nature that can be associated with a syndrome, precipitated by the presence of a germline mutation. Familial forms of the disease are usually seen with mutations of SDHx genes, especially the SDHD gene. SDHB mutations are predisposed to malignant tumors. We found 6 patients with multiple tumors amongst 30 patients with HNPGLs during the period of 2016 to 2021. We discuss the phenotypic and genetic patterns in our patients with multiple HNPGLs and explore the management possibilities related to the disease. Fifty percent of our patients had incidental findings of HNPGLs. Twenty-one biochemically silent tumors were found. Four patients had germline mutations, and only one had a positive family history. Three out of five underwent surgery without permanent complications. Preventative measures (genetic counselling and tumor surveillance) represent the gold standard in effectively controlling the disease in index patients and their relatives. In terms of treatment, apart from surgical and radiotherapeutic interventions, new therapeutic measures such as gene targeted therapy have contributed very sparsely. With the lack of standardized protocols, management of patients with multiple HNPGLs still remains very challenging, especially in those with sporadic or malignant forms of the disease. Full article

(This article belongs to the Special Issue Head and Neck Tumors)

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11 pages, 997 KiB

Open AccessArticle

High Levels of Low-Density Lipoproteins Correlate with Improved Survival in Patients with Squamous Cell Carcinoma of the Head and Neck

by Torben Wilms, Linda Boldrup, Xiaolian Gu, Philip J. Coates, Nicola Sgaramella and Karin Nylander

Biomedicines 2021, 9(5), 506; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050506 - 04 May 2021

Cited by 6 | Viewed by 1860

Abstract

Circulating lipoproteins as risk factors or prognostic indicators for various cancers have been investigated previously; however, no clear consensus has been reached. In this study, we aimed at evaluating the impact of serum lipoproteins on the prognosis of patients with squamous cell carcinoma of the head and neck (SCCHN). Levels of total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides and lipoprotein(a) were measured in serum samples from 106 patients and 28 healthy controls. We found that HDL was the only lipoprotein exhibiting a significant difference in concentration between healthy controls and patients (p = 0.012). Kaplan–Meier survival curves indicated that patients with high levels of total cholesterol or LDL had better overall survival than patients with normal levels (p = 0.028 and p = 0.007, respectively). Looking at patients without lipid medication (n = 89) and adjusting for the effects of TNM stage and weight change, multivariate Cox regression models indicated that LDL was an independent prognostic factor for both overall (p = 0.005) and disease-free survival (p = 0.013). In summary, our study revealed that high LDL level is beneficial for survival outcome in patients with SCCHN. Use of cholesterol-lowering medicines for prevention or management of SCCHN needs to be evaluated carefully. Full article

(This article belongs to the Special Issue Head and Neck Tumors)

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15 pages, 3260 KiB

Open AccessArticle

Fas-Fas Ligand Interplay in the Periphery of Salivary Gland Carcinomas as a New Checkpoint Predictor for Disease Severity and Immunotherapy Response

by Zuzana Strizova, Martin Kuchar, Linda Capkova, Martin Komarc, Jiri Skrivan, Jirina Bartunkova, Jan Plzak and Daniel Smrz

Biomedicines 2021, 9(4), 402; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9040402 - 08 Apr 2021

Cited by 7 | Viewed by 2210

Abstract

Salivary gland carcinomas (SGCs) are extremely morphologically heterogeneous, and treatment options for this disease are limited. Immunotherapy with immune checkpoint inhibitors (ICIs) represents a revolutionary treatment approach. However, SGCs remain largely resistant to this therapy. An increasing body of evidence suggests that resistance to ICI therapy is modulated by the Fas (CD95)–Fas ligand (FasL, CD178) interplay between tumor cells and immune cells. In this study, we examined the Fas–FasL interplay between tumor cells and tumor-infiltrating immune cells (TIICs) in the center and periphery of SGCs from 62 patients. We found that the Fas-expressing tumor cells accumulated in the center of SGC tumors with increasing tumor stage. Furthermore, this accumulation occurred regardless of the presence of TIICs expressing high levels of FasL. On the contrary, a loss of Fas-expressing TIICs with increasing tumor stage was found in the tumor periphery, whereas FasL expression in tumor cells in the tumor periphery correlated with tumor stage. These data suggest that SGC cells are resistant to FasL-induced apoptosis by TIICs but could utilize FasL to eliminate these cells in high-stage tumors to provide resistance to immunotherapy. Full article

(This article belongs to the Special Issue Head and Neck Tumors)

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14 pages, 2471 KiB

Open AccessArticle

The Periphery of Salivary Gland Carcinoma Tumors Reveals a PD-L1/PD-1 Biomarker Niche for the Evaluation of Disease Severity and Tumor—Immune System Interplay

by Martin Kuchar, Zuzana Strizova, Linda Capkova, Martin Komarc, Jiri Skrivan, Jirina Bartunkova, Daniel Smrz and Jan Plzak

Biomedicines 2021, 9(2), 97; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020097 - 20 Jan 2021

Cited by 8 | Viewed by 2228

Abstract

The treatment options for patients with advanced salivary gland cancers (SGCs) are limited. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, the response to ICI immunotherapy is largely driven by the immune cell signatures within the tumor tissue and the para-tumoral tissue compartments. To date, there are no data on the expression of programed cell death protein-1/programed cell death protein-ligand 1 (PD-1/PD-L1) in SGC, which may enable the implementation of ICI immunotherapy for this disease. Thus, we performed an immunohistochemical analysis of PD-1 and PD-L1 expression in tumor cells and tumor-infiltrating immune cells (TIICs) in the tumor center and periphery of 62 SGC patients. The tumor periphery showed significantly higher expression of PD-L1 in tumor cells than in TIICs. Moreover, peripheral TIICs had significantly higher PD-1 expression than peripheral tumor cells. PD-1-positive tumor cells were detected exclusively in the tumor center of high-grade tumors, and most importantly, the presence of lymph node (LN) metastases and primary tumor stage significantly correlated with the presence of PD-L1-positive tumor cells in the tumor periphery. The PD-1/PD-L1 molecular signatures in SGC are clustered predominantly in the tumor periphery, reflect disease severity, and may predict the response to ICI immunotherapy in SGC patients. Full article

(This article belongs to the Special Issue Head and Neck Tumors)

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Review

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12 pages, 316 KiB

Open AccessReview

Liquid Biopsy as a Tool for the Characterisation and Early Detection of the Field Cancerization Effect in Patients with Oral Cavity Carcinoma

by Elisabeth Pérez-Ruiz, Vanesa Gutiérrez, Marta Muñoz, Javier Oliver, Marta Sánchez, Laura Gálvez-Carvajal, Antonio Rueda-Domínguez and Isabel Barragán

Biomedicines 2021, 9(10), 1478; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101478 - 15 Oct 2021

Cited by 2 | Viewed by 1956

Abstract

Oral squamous cell carcinoma (OSCC) constitutes approximately 25% of all head and neck cancer, for which the consumption of tobacco and alcohol are the main associated risk factors. The field cancerization effect of OSCC is one of the main reasons for the poor survival rates associated with this disease. Despite some advances, its ccharacterization and early diagnosis continue to challenge modern oncology, and the goal of improving the prognosis remains to be achieved. Among new early diagnostic tools for OSCC that have been proposed, liquid biopsy appears to be an ideal candidate, as studies have shown that the analysis of blood and saliva provides promising data for the early detection of relapses or second tumours. Full article

(This article belongs to the Special Issue Head and Neck Tumors)

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13 pages, 1931 KiB

Open AccessReview

Tumor-Infiltrating Lymphocytes in the Tumor Microenvironment of Laryngeal Squamous Cell Carcinoma: Systematic Review and Meta-Analysis

by Juan P. Rodrigo, Mario Sánchez-Canteli, Fernando López, Gregory T. Wolf, Juan C. Hernández-Prera, Michelle D. Williams, Stefan M. Willems, Alessandro Franchi, Andrés Coca-Pelaz and Alfio Ferlito

Biomedicines 2021, 9(5), 486; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050486 - 28 Apr 2021

Cited by 27 | Viewed by 2522

Abstract

The presence of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment has been demonstrated to be of prognostic value in various cancers. In this systematic review and meta-analysis, we investigated the prognostic value of TIL in laryngeal squamous cell carcinoma (LSCC). We performed a systematic search in PubMed for publications that investigated the prognostic value of TIL in LSCC. A meta-analysis was performed including all studies assessing the association between TIL counts in hematoxylin-eosin (HE)-stained sections, for CD8+ and/or CD3+/CD4+ TIL and overall survival (OS) or disease-free survival (DFS). The pooled meta-analysis showed a favorable prognostic role for stromal TIL in HE sections for OS (HR 0.57, 95% CI 0.36–0.91, p = 0.02), and for DFS (HR 0.56, 95% CI 0.34–0.94, p = 0.03). High CD8+ TIL were associated with a prolonged OS (HR 0.62, 95% CI 0.4–0.97, p = 0.04) and DFS (HR 0.73, 95% CI 0.34–0.94, p = 0.002). High CD3+/CD4+ TIL demonstrated improved OS (HR 0.32, 95% CI 0.16–0.9, p = 0.03) and DFS (HR 0.23, 95% CI 0.10–0.53, p = 0.0005). This meta-analysis confirmed the favorable prognostic significance of TIL in LSCC. High stromal TIL evaluated in HE sections and intra-tumoral and stromal CD3+, CD4+ and/or CD8+ TIL might predict a better clinical outcome. Full article

(This article belongs to the Special Issue Head and Neck Tumors)

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12 pages, 423 KiB

Open AccessSystematic Review

Gene Mutations in Circulating Tumour DNA as a Diagnostic and Prognostic Marker in Head and Neck Cancer—A Systematic Review

by Markéta Hudečková, Vladimír Koucký, Jan Rottenberg and Břetislav Gál

Biomedicines 2021, 9(11), 1548; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9111548 - 27 Oct 2021

Cited by 11 | Viewed by 2047

Abstract

(1) Background: Head and Neck Squamous Cell Carcinoma (HNSCC) is one of the most common malignancies globally. An early diagnosis of this disease is crucial, and the detection of gene mutations in circulating tumour DNA (ctDNA) through a liquid biopsy is a promising non-invasive diagnostic method. This review aims to provide an overview of ctDNA mutations in HNSCC patients and discuss the potential use of this tool in diagnosis and prognosis. (2) Methods: A systematic search for articles published in the English language between January 2000 and April 2021 in the Medline and Scopus databases was conducted. (3) Results: A total of 10 studies published in nine publications were selected and analysed. Altogether, 390 samples were obtained from HNSCC patients, and 79 control samples were evaluated. The most often explored gene mutation in ctDNA was TP53. (4) Conclusions: The examination of a larger group of gene mutations and the use of a combination of multiple detection methods contribute to a higher detection rate of mutated ctDNA. More studies are necessary to verify these conclusions and to translate them into clinical practice. Full article

(This article belongs to the Special Issue Head and Neck Tumors)

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