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Special Issue "Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21th Century of Oncology"

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: 30 November 2020.

Special Issue Editor

Prof. Dr. Sven Perner
Website
Guest Editor
1. University Hospital Schleswig Holstein, Campus Luebeck, Institute of Pathology, Ratzeburger Allee 160 (Building 50), 23538 Luebeck, Germany
2. Research Center Borstel, Department of Pathology, Parkallee 3a, 23845 Borstel, Germany
Interests: prostate cancer; lung cancer; head and neck cancer; molecular biology; molecular pathology; biomarker; immunoncology

Special Issue Information

Dear Colleagues,

Squamous cell carcinoma of the head and neck region (HNSCC) is the sixth most common cancer entity world-wide. However, despite achievements in other malignancies, the therapeutic options for HNSCC have still not been properly developed. Surgery or platin-based radiochemo therapy are incriminatory and often mutilating for patients. New therapeutic approaches such as immune check point inhibitors and kinase inhibitors do not have as much of an impact on HNSCC as on other tumor entities. This Issue focuses on deciphering the molecular basis of HNSCC in order to develop new alternative therapeutic options and biomarkers for early detection and risk stratification of primary and recurrent HNSCC. New therapeutic approaches are necessary, since the two-year survival of grade III and IV tumors is still only 30%. In particular, having reliable biomarkers to assess the risk for the clinically challenging existence of occult lymph node metastasis would be an important clinical tool to decide whether surgery or irradiation of the neck is necessary. The clinical follow-up of HNSCC patients is still based on clinical examination, ultrasound, and x-ray, while there is still no established biomarker for the detection of disease recurrence.

For this Issue, we would like to invite researchers and clinicians to submit their work in order to enlighten this heavily under researched field of HNSCC. 

Prof. Dr. Sven Perner
Guest Editor

Manuscript Submission Information

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Published Papers (8 papers)

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Research

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Open AccessArticle
NR2F6 as a Prognostic Biomarker in HNSCC
Int. J. Mol. Sci. 2020, 21(15), 5527; https://doi.org/10.3390/ijms21155527 - 01 Aug 2020
Abstract
Head and neck squamous cell carcinoma (HNSCC)is the 6th most common cancer in humans worldwide and is associated with a poor prognosis for patients. NR2F6 has been identified as an immune checkpoint molecule in tumor-infiltrating T lymphocytes and is associated with a poor [...] Read more.
Head and neck squamous cell carcinoma (HNSCC)is the 6th most common cancer in humans worldwide and is associated with a poor prognosis for patients. NR2F6 has been identified as an immune checkpoint molecule in tumor-infiltrating T lymphocytes and is associated with a poor prognostic outcome in various cancers. The prognostic value of NR2F6 in HNSCC has not been described yet. We used a large, representative and clinically well-characterized cohort of 383 HNSCC patients, of which 22.4% developed a local recurrence. The NR2F6 expression was analyzed by using immunohistochemistry and was afterward correlated with clinical characteristics and clinicopathological features of HNSCC patients. Primary tumors from patients who develop a local recurrence have a higher NR2F6 expression than primary tumors which do not develop a local recurrence. Furthermore, a high NR2F6 expression is associated with poorer recurrence-free survival, although there is no correlation with overall survival. NR2F6 expression is independent of the T stage and UICC stage. NR2F6 might be a new prognostic biomarker for the early detection of local recurrences in HNSCC patients. Therefore, it may help to improve the recognition of patients who would benefit from more frequent follow-up examinations. Full article
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Open AccessArticle
CDK19 as a Potential HPV-Independent Biomarker for Recurrent Disease in HNSCC
Int. J. Mol. Sci. 2020, 21(15), 5508; https://doi.org/10.3390/ijms21155508 - 31 Jul 2020
Abstract
The Mediator complex is a central integrator of transcription and a hub for the regulation of gene expression. Cyclin dependent kinase (CDK) 19 and its paralog CDK8 are part of its kinase domain and contribute to cancer progression in different cancer entities. STAT1 [...] Read more.
The Mediator complex is a central integrator of transcription and a hub for the regulation of gene expression. Cyclin dependent kinase (CDK) 19 and its paralog CDK8 are part of its kinase domain and contribute to cancer progression in different cancer entities. STAT1 is an important immune modulator and a downstream substrate of CDK8/CDK19 mediated phosphorylation. So far, little is known about CDK19’s role in head and neck squamous cell carcinoma (HNSCC) progression, its link to STAT1 activity, and related immune modulation. Immunohistochemistry for CDK19, activated pSTAT1, and PD-L1, known to be affected by STAT1, was conducted on samples of 130 primary tumors, 71 local recurrences, 32 lymph node metastases, and 25 distant metastases of HNSCC. Compared to primary tumors, CDK19 is overexpressed in local recurrences and distant metastases as well as in primary tumors that developed local recurrence after initial therapy. Patients with high-CDK19-expressing primary tumors have a significantly shorter disease-free survival. CDK19 expression correlates with pSTAT1 expression in primary tumors associated with recurrent disease, local recurrent tumors, lymph node metastases, and distant metastases. pSTAT1 expression correlates with PD-L1 expression in recurrent tumors. Our findings identify CDK19 as a potential biomarker in HNSCC to predict recurrent disease and support recent developments to target CDK19 and its paralog CDK8 in advanced cancer. Full article
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Open AccessArticle
PD-L1 Expression and a High Tumor Infiltrate of CD8+ Lymphocytes Predict Outcome in Patients with Oropharyngeal Squamous Cells Carcinoma
Int. J. Mol. Sci. 2020, 21(15), 5228; https://doi.org/10.3390/ijms21155228 - 23 Jul 2020
Abstract
Carcinogenesis of human papillomavirus (HPV)-related (+) oropharyngeal squamous cell carcinoma (OPSCC) differs from HPV-negative (–) OPSCC. HPV-related immune-escape-mechanism could be responsible for the development and progression of HPV+ tumors and an immunophenotype different from HPV– OPSCC is expected. The purpose of this study [...] Read more.
Carcinogenesis of human papillomavirus (HPV)-related (+) oropharyngeal squamous cell carcinoma (OPSCC) differs from HPV-negative (–) OPSCC. HPV-related immune-escape-mechanism could be responsible for the development and progression of HPV+ tumors and an immunophenotype different from HPV– OPSCC is expected. The purpose of this study was to analyze the expression of programmed cell death protein 1 ligand 1 (PD-L1) and its prognostic relevance in relation to CD8+ tumor infiltrating lymphocytes (TILs) and the major histocompatibility complex (MHC) I expression in OPSCC. We quantified PD-L1 expression on tumor cells (TC) and macrophages and MHC I expression in association to CD8+ TILs by immunohistochemistry on tissue microarray derived from 171 HPV+/-OPSCC. HPV-status was determined by p16INK4a immunohistochemistry/HPV-DNA detection. Presence of CD8+ TILs, PD-L1 expression on TC, and a more frequent loss of MHC I in HPV+ compared to HPV- OPSCC was detected. A high amount of CD8+ TILs in the whole cohort and in HPV+ OPSCC and PD-L1 expression on TC in HPV- OPSCC was associated with favorable overall survival. There was a trend for an improved outcome according to PD-L1 expression (macrophages) in HPV+ OPSCC without reaching statistical significance. CD8+ TILs and PD-L1-expression have prognostic impact in OPSCC and might present useful biomarkers for predicting clinical outcome and personalized therapy concepts. Full article
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Open AccessArticle
Immune Checkpoint Expression on Immune Cells of HNSCC Patients and Modulation by Chemo- and Immunotherapy
Int. J. Mol. Sci. 2020, 21(15), 5181; https://doi.org/10.3390/ijms21155181 - 22 Jul 2020
Abstract
Endogenous control mechanisms, including immune checkpoints and immunosuppressive cells, are exploited in the process of tumorigenesis to weaken the anti-tumor immune response. Cancer treatment by chemotherapy or immune checkpoint inhibition can lead to changes of checkpoint expression, which influences therapy success. Peripheral blood [...] Read more.
Endogenous control mechanisms, including immune checkpoints and immunosuppressive cells, are exploited in the process of tumorigenesis to weaken the anti-tumor immune response. Cancer treatment by chemotherapy or immune checkpoint inhibition can lead to changes of checkpoint expression, which influences therapy success. Peripheral blood lymphocytes (PBL) and tumor-infiltrating lymphocytes (TIL) were isolated from head and neck squamous cell carcinoma (HNSCC) patients (n = 23) and compared to healthy donors (n = 23). Immune checkpoint expression (programmed cell death ligand 1 (PD-1), tumor necrosis factor receptor (TNFR)-related (GITR), CD137, tumor necrosis factor receptor superfamily member 4 (TNFRSF4) (OX40), t-cell immunoglobulin and mucin-domain containing-3 (TIM3), B- and T-lymphocyte attenuator (BTLA), lymphocyte-activation gene 3 (LAG3)) was determined on immune cells by flow cytometry. PD-L1 expression was detected on tumor tissue by immunohistochemistry. Immune cells were treated with immuno- and chemotherapeutics to investigate treatment-specific change in immune checkpoint expression, in vitro. Specific changes of immune checkpoint expression were identified on PBL and TIL of HNSCC patients compared to healthy donors. Various chemotherapeutics acted differently on the expression of immune checkpoints. Changes of checkpoint expression were significantly less pronounced on regulatory T cells compared to other lymphocyte populations. Nivolumab treatment significantly reduced the receptor PD-1 on all analyzed T cell populations, in vitro. The specific immune checkpoint expression patterns in HNSCC patients and the investigated effects of immunomodulatory agents may improve the development and efficacy of targeted immunotherapy. Full article
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Open AccessArticle
Impact of SRY-Box Transcription Factor 11 Gene Polymorphisms on Oral Cancer Risk and Clinicopathologic Characteristics
Int. J. Mol. Sci. 2020, 21(12), 4468; https://doi.org/10.3390/ijms21124468 - 23 Jun 2020
Abstract
Oral cancer is among the most common cancers worldwide and has become a major global health problem because of its relatively high morbidity and mortality rates. The sex-determining region on the Y-chromosome-related high-mobility-group box (SOX) transcription factor 11 (SOX11) plays a key role [...] Read more.
Oral cancer is among the most common cancers worldwide and has become a major global health problem because of its relatively high morbidity and mortality rates. The sex-determining region on the Y-chromosome-related high-mobility-group box (SOX) transcription factor 11 (SOX11) plays a key role in human development and differentiation and is frequently increased in various human cancers. However, the clinical significance of SOX11 polymorphisms in oral cancer and their association with oral cancer risk are unclear. In this study, we included 1196 patients with oral cancer and 1200 controls. Real-time polymerase chain reaction was applied to analyze three SOX11 single-nucleotide polymorphisms (rs77996007, rs66465560, and rs68114586). Our results shown that SOX11 polymorphisms carriers with betel quid chewing were found to have an 8.38- to 9.23-fold risk to have oral cancer compared to SOX11 wild-type carriers without betel quid chewing. Furthermore, oral cancer patients who carried SOX11 rs77996007 “TC + CC” variants were significantly associated with large tumor size (AOR, 1.324; 95% CI, 1.047–1.674; p = 0.019). Moreover, a database analysis using the Cancer Genome Atlas suggested that SOX11 mRNA expression was high during the tumor development process. In conclusion, our results suggest that SOX11 rs77996007 is involved in oral cancer progression and clinical characteristics. Full article
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Open AccessArticle
EVI1 as a Marker for Lymph Node Metastasis in HNSCC
Int. J. Mol. Sci. 2020, 21(3), 854; https://doi.org/10.3390/ijms21030854 - 28 Jan 2020
Abstract
Background: HNSCC is the sixth most common cancer in humans and has still a very poor prognosis. The treatment methods so far are very often associated with mutilation and impairment in the quality of life. Except for p16 expression, there are no reliable [...] Read more.
Background: HNSCC is the sixth most common cancer in humans and has still a very poor prognosis. The treatment methods so far are very often associated with mutilation and impairment in the quality of life. Except for p16 expression, there are no reliable prognostic markers in HNSCC so far. Ecotropic Viral Integration Site 1 (EVI1) is a well-described prognostic marker in leukemia and different types of solid cancers. In these, a high EVI1 expression is associated with a poor prognosis. In HNSCC, it is not known so far if EVI1 has any prognostic relevance. Materials and Methods: We used our representative tissue cohort of 389 primary HNSCCs, of which 57.2% had one or more lymph node metastases. Here EVI1 expression was analyzed via immunohistochemistry and correlated with the clinical characteristics of these patients. Results: Although in HNSCC EVI1 expression does not predict poor survival, a high EVI1 expression in the primary tumor correlates with a lymph node metastatic disease. Conclusion: Consequently, EVI1 may serve as a biomarker to predict an occult lymph node metastasis in a clinical nodal negative (cN0) HNSCC. Full article
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Review

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Open AccessReview
The Emerging Role of Exosomes in Diagnosis, Prognosis, and Therapy in Head and Neck Cancer
Int. J. Mol. Sci. 2020, 21(11), 4072; https://doi.org/10.3390/ijms21114072 - 06 Jun 2020
Abstract
Exosomes, the smallest group of extracellular vesicles, carry proteins, miRNA, mRNA, DNA, and lipids, which they efficiently deliver to recipient cells, generating a communication network. Exosomes strongly contribute to the immune suppressive tumor microenvironment of head and neck squamous cell carcinomas (HNSCC). Isolation [...] Read more.
Exosomes, the smallest group of extracellular vesicles, carry proteins, miRNA, mRNA, DNA, and lipids, which they efficiently deliver to recipient cells, generating a communication network. Exosomes strongly contribute to the immune suppressive tumor microenvironment of head and neck squamous cell carcinomas (HNSCC). Isolation of exosomes from HNSCC cell culture or patient’s plasma allows for analyzing their molecular cargo and functional role in immune suppression and tumor progression. Immune affinity-based separation of different exosome subsets, such as tumor-derived or T cell-derived exosomes, from patient’s plasma simultaneously informs about tumor status and immune dysfunction. In this review, we discuss the recent understanding of how exosomes behave in the HNSCC tumor microenvironment and why they are promising liquid biomarkers for diagnosis, prognosis, and therapy in HNSCC. Full article
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Open AccessReview
Special Issue about Head and Neck Cancers: HPV Positive Cancers
Int. J. Mol. Sci. 2020, 21(9), 3388; https://doi.org/10.3390/ijms21093388 - 11 May 2020
Cited by 1
Abstract
The oropharynx has become the leading primary site for Human Papilloma Virus (HPV)-associated head and neck cancer. HPV positive oropharyngeal squamous cell carcinoma (HPV+ OSCC) has emerged as an epidemic not easily recognized by many physicians, resulting in delays in diagnosis and management. [...] Read more.
The oropharynx has become the leading primary site for Human Papilloma Virus (HPV)-associated head and neck cancer. HPV positive oropharyngeal squamous cell carcinoma (HPV+ OSCC) has emerged as an epidemic not easily recognized by many physicians, resulting in delays in diagnosis and management. HPV+ OSCC traditionally refers to younger, healthier patients with high economic status and high-risk sexual behavior and is related to improved prognosis. De-intensification strategies are being evaluated in ongoing clinical trials and if validated, might help spare severe morbidity associated with current cisplatin-based chemoradiotherapy, which is the standard of care for all patients with locally advanced head and neck cancer. On the other hand, whether HPV status represents an important prognostic factor for non-oropharyngeal sites remains to be elucidated. Full article
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