The opposing roles of NOTCH signalling in head and neck cancer: a mini review

NOTCH signalling can exert oncogenic or tumour suppressive effects in both solid and haematological malignancies. Similar to T‐cell acute lymphoblastic leukaemia (T‐ALL), early studies suggested a pro‐tumorigenic role of NOTCH in head and neck squamous cell carcinoma (HNSCC), mainly based on the increased expression levels of the genes within the pathway. Recently, data from exome sequencing analyses unexpectedly pointed to a tumour suppressor role for NOTCH in HNSCC by identifying loss‐of‐function mutations in the NOTCH1 gene in a significant proportion of patients. These data have questioned the accepted role of NOTCH in HNSCC and the possible rationale of targeting NOTCH in this disease. This review summarises the current information on NOTCH signalling in HNSCC and discusses how this pathway can apparently exert opposing effects within the same disease.     

MicroRNA‐137 promoter methylation in oral lichen planus and oral squamous cell carcinoma

Oral lichen planus (OLP) is a common oral mucosal disease, which is generally considered a potentially malignant lesion. To identify efficiently prognostic biomarker, we investigated the microRNA‐137 (miR‐137) promoter methylation in OLP and compared with the samples from healthy volunteers and patients with oral squamous cell carcinoma (OSCC). A total of 20 OLP and 12 patients with OSCC as well as 10 healthy subjects were subjected to miR‐137 promoter methylation analysis using methylation‐specific PCR (MSP). To address the malignancy prediction potential from miR‐137 promoter methylation status, methylation of the p16 gene, a well‐known tumor suppressor, was investigated in the same samples. The p16 methylation and miR‐137 promoter methylation were found to be 25% and 35% in patients with OLP, 50% and 58.3% in patients with OSCC, and 0% and 0% in healthy subjects, respectively. The differences between miR‐137 and p16 methylation levels were statistically significant between healthy controls and patients. Methylation levels of the two promoters were also influenced by age, gender, and lesion duration. Interestingly, aberrant promoter methylation of the p16 and miR‐137 genes was only found in the epithelium but not in the connective tissue from patients with OLP. This raises the possibility to use miR‐137 methylation as a biomarker for malignant prediction in patients with OLP.     

The role of NEFL in cell growth and invasion in head and neck squamous cell carcinoma cell lines

The neurofilament light polypeptide (NEFL) gene located on chromosome 8q21 is associated with the cancer of several organs and is regarded as a potential tumor suppressor gene. However, the role of the NEFL protein has not yet been studied in cancer cells. Although evidence suggests that there is a correlation between NEFL expression and cancer, studies regarding the role of the NEFL protein have been mostly limited to neurological diseases, such as Charcot–Marie–Tooth's disease (CMT). Most of these studies have not explored the role of NEFL in cancer cell apoptosis and/or invasion. In this study, NEFL expression was manipulated, and apoptosis and invasion were compared in head and neck squamous cell carcinoma cell lines. The results show that the expression of NEFL induces cancer cell apoptosis and inhibits invasion in these cell lines, suggesting that NEFL may play a role in cancer cell apoptosis and invasion.     

Laser ionization mass spectrometry in oral squamous cell carcinoma

Biomarker research in oral squamous cell carcinoma (OSCC) aims for screening/early diagnosis and in predicting its recurrence, metastasis and overall prognosis. This article reviews the current molecular perspectives and diagnosis of oral cancer with proteomics using matrix‐assisted laser desorption ionization (MALDI) and surface‐enhanced laser desorption ionization (SELDI) mass spectrometry (MS). This method shows higher sensitivity, accuracy, reproducibility and ability to handle complex tissues and biological fluid samples. However, the data interpretation tools of contemporary mass spectrometry still warrant further improvement. Based on the data available with laser‐based mass spectrometry, biomarkers of OSCC are classified as (i) diagnosis and prognosis, (ii) secretory, (iii) recurrence and metastasis, and (iv) drug targets. Majority of these biomarkers are involved in cell homeostasis and are either physiologic responders or enzymes. Therefore, proteins directly related to tumorigenesis have more diagnostic value. Salivary secretory markers are another group that offers a favourable and easy strategy for non‐invasive screening and early diagnosis in oral cancer. Key molecular inter‐related pathways in oral carcinogenesis are also intensely researched with software analysis to facilitate targeted drug therapeutics. The review suggested the need for incorporating ‘multiple MS or tandem approaches’ and focusing on a ‘group of biomarkers’ instead of single protein entities, for making early diagnosis and treatment for oral cancer a reality.     

Vaccine-based approaches to squamous cell carcinoma of the head and neck

Vaccine-based approaches for the treatment of advanced squamous cell carcinoma of the head and neck have achieved very limited success. Improvement in vaccine efficacy for both diseases control and survival is predicated on a careful analysis of the root causes for successes and failures to date. In this review, we analyse the utility and limitations of select protective and therapeutic vaccine strategies for tumour prevention and therapy. Based on this characterisation, we define potential directions which are meritorious of future study.     

Co‐inhibitory immune checkpoints in head and neck squamous cell carcinoma

The upregulation of co‐inhibitory immune checkpoints hampers the immune response toward tumor cells and facilitates the tumor cells ability to evade immunosurveillance. Specific inhibitory immune checkpoint delivers inhibitory signals to T cells using multiple mechanisms. More in‐depth understanding of the co‐inhibitory immune checkpoints could be exploited for head and neck squamous cell carcinoma (HNSCC) treatment. In this review, we summarize the expression and the mechanism of partial co‐inhibitory immune checkpoint signals and discuss targeting co‐inhibitory immune checkpoints as an immunotherapeutic target for cancer therapy. This review may provide a better understanding of the co‐inhibitory immune checkpoints and could promote applications of immunotherapy.     

Overexpression of CD147 contributes to the chemoresistance of head and neck squamous cell carcinoma cells

Head and neck cancer is the sixth most common cancer in the world and most of them are squamous cell carcinomas. High frequency of cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) leads to tumor relapse and irresponsiveness to cisplatin‐based chemotherapy. However, the mechanisms underlying cisplatin resistance is still largely unrevealed. In this study, we found that CD147 was overexpressed in cisplatin‐resistant HNSCC cell lines. Based on the result, CD147 expression was down‐regulated in the cisplatin‐resistant cell line and we observed that the sensitivity to cisplatin increased, as showed in the results of MTT assay and PI‐staining apoptotic detection. Meanwhile, transfection of CD147 expression vector promoted the occurrence of cisplatin resistance in the cisplatin‐sensitive cell line. Simultaneously blocking of uPAR with neutralizing antibody would significantly prevent the occurrence of cisplatin resistance induced by CD147 overexpression. In conclusion, our study finds that CD147 is also involved in mediating cisplatin resistance in HNSCC and uPAR serves as a possible candidate that collaborates with CD147 in this process.     

Fatal course of tonsillar squamous cell carcinoma associated with Fanconi anaemia: a mini review

Fanconi anaemia (FA) is a rare genetic syndrome characterized by progressive pancytopenia, variably expressed congenital abnormalities and susceptibility, amongst others, to solid tumours. Early detection by oral health professionals of a pathological process can have a critical impact on the clinical course of that condition. In this paper we report the case of a 27-year-old male patient with tonsillar squamous cell carcinoma (cT4 cN2b cM0 G3) associated with FA. Due to the locally advanced growth of the tumour and the poor systemic condition we ruled out primary surgery and settled for primary radio- and chemotherapy. Given the poor clinical course a focus on the aspect of secondary prevention is reasonable, given that it is known that patients with FA are at higher risk of developing malignancy than the general population. A multi-disciplinary approach is necessary in which the prevention of, surveillance for and the treatment of malignancies are important aspects of management and may improve disease-free survival.     

Circulating markers in squamous cell carcinoma of the head and neck: A review

Biological markers of disease enhance the ability to diagnose, treat and evaluate results of therapy and are especially intriguing for their potential use in the management of malignant tumours. The serum levels of various biochemical substances have been shown to be abnormal for many cancers and are utilised in the management of affected patients. Several markers have been thoroughly investigated for potential clinical utility in head and neck carcinoma. Although no single marker has been found to be adequately sensitive and specific, combinations of markers may improve the utility for some aspects of patient management. This review highlights the literature to date in the realm of circulating markers for head and neck carcinoma. A discussion of the potential usefulness and limitations of such markers follows.     

Cigarette smoke extract induces oral squamous cell carcinoma cell invasion in a receptor for advanced glycation end‐products‐dependent manner

Oral squamous cell carcinoma (OSCC) affects approximately 30,000 people and is associated with tobacco use. Little is known about the mechanistic effects of second‐hand smoke in the development of OSSC. The receptor for advanced glycation end‐products (RAGE) is a surface receptor that is upregulated by second‐hand smoke and inhibited by semi‐synthetic glycosaminoglycan ethers (SAGEs). Our objective was to determine the role of RAGE during cigarette smoke extract‐induced cellular responses and to use SAGEs as a modulating factor of Ca9‐22 OSCC cell invasion. Ca9‐22 cells were cultured in the presence or absence of cigarette smoke extract and SAGEs. Cell invasion was determined and cells were lysed for western blot analysis. Ras and nuclear factor of kappa light polypeptide gene enhancer in B‐cells (NF‐κB) activation were determined. Treatment of cells with cigarette smoke extract resulted in: (i) increased invasion of OSCC; (ii) increased RAGE expression; (iii) inhibition of cigarette smoke extract‐induced OSCC cell invasion by SAGEs; (iv) increased Ras, increased AKT and NF‐κB activation, and downregulation by SAGEs; and (v) increased expression of matrix metalloproteinases (MMPs) 2, 9, and 14, and downregulation by SAGEs. We conclude that cigarette smoke extract increases invasion of OSCC cells in a RAGE‐dependent manner. Inhibition of RAGE decreases the levels of its signaling molecules, which results in blocking the cigarette smoke extract‐induced invasion.     

Stem cells in head and neck squamous cell carcinoma

The existence of a small subpopulation of tumourigenic cancer stem cells in the bulk of human head and neck squamous cancers (SCC) has been recognised in recent reports. This subpopulation has self-renewal properties and is responsible for the production of differentiated daughter cells that form the bulk of the tumour. Stem cells in head and neck SCC can be identified functionally using their self-renewal properties, or by their characteristic surface markers. As their resistance to contemporary cancer treatments may eventually lead to the failure of treatment there is an urgent need to better understand their biology with the ultimate goal of developing new diagnostic markers and curative cancer treatments.