Somatic evolution of head and neck cancer – Biological robustness and latent vulnerability

Despite recent advancements in multidisciplinary treatments, the overall survival and quality of life of patients with advanced head and neck squamous cell carcinoma (HNSCC) have not improved significantly over the past decade. Molecular targeted therapies, which have been addressed and advanced by the concept of “oncogene addiction”, have demonstrated only limited successes so far. To explore a novel clue for clinically effective targeted therapies, we analyzed the molecular circuitry of HNSCC through the lens that HNSCC is an evolving system. In the trajectory of this somatic evolution, HNSCC acquires biological robustness under a variety of selective pressures including genetic, epigenetic, micro-environmental and metabolic stressors, which well explains the major mechanism of “escaping from oncogene addiction”. On the other hand, this systemic view appears to instruct us approaches to target latent vulnerability of HNSCC that is masked behind the plasticity and evolvability of this complex adaptive system.     

Malignant mucosal melanoma of the head and neck — a review

Mucosal melanomas comprise about 1% of all malignant melanomas and exhibit far more aggressive behaviour than that of skin melanomas: they are more inclined to metastatize into regional and distant sites or recur locally, regionally or in distant locations, resulting in a high rate of cause-specific death. Mucosal melanomas in the head and neck region account for half of all mucosal melanomas, occurring mainly in the upper respiratory tract, oral cavity and pharynx. They appear with equal gender distribution and with a peak incidence in the age range 60-80 years. In consequence of their hidden location, they are usually diagnosed in a locoregionally advanced clinical stage, with a rate of 5-48% of regional and 4-14% of distant dissemination. The typical therapeutic approach is surgery, postoperative irradiation and systemic therapy. Local control with either surgery or radiotherapy is frequently (60- 70%) achieved, but the rates of local, regional and distant recurrences are high (50-90%, 20-60% and 30-70%, respectively). The reported 5-year actual survival rates are poor (17-48%), which is attributed mainly to a haematogenous dissemination. These characteristics demonstrate that identification of the precursor lesions and more effective local and systemic approaches are needed to improve the therapeutic results.     

“Watch-and-see” policy for the clinically positive neck in head and neck cancer treated with chemoradiotherapy

Background Chemoradiotherapy (CRT) is becoming more widely used for head and neck cancer. However, there are conflicting theories regarding the best management options for patients with advanced nodal disease. Methods From 1990 to 1999, we treated 96 patients with N1-N2 neck disease by concomitant CRT for organ preservation, using weekly carboplatin or a low daily dose of cisplatin, followed by a “watch-and-see” policy for the neck. In the present study, we retrospectively analyzed the treatment outcome in 63 of these patients who received definitive CRT for primary and neck diseases and were monitored for neck disease for more than 2 years. Results In 12 of the 22 (55%) N1 patients, CRT successfully controlled the neck disease. CRT was successful in 18 of the 41 (44%) patients with N2 disease. In 6 (60%) of 10 patients with residual or recurrent N1 disease, salvage surgery was successful. Of the 23 patients with residual or recurrent N2 disease, salvage surgery was successful in 8 patients (35%). The group of patients who showed a clinical complete response (CCR) to CRT had an overall survival rate of 62.4% (33 patients), whereas for those with a less than complete response (<CCR), the figure was 13.3% (30 patients; P < 0.001). Among the <CCR-neck group, patients who underwent neck dissection (ND) as well (n = 20) did not have a significantly better overall survival than those who did not undergo ND (n = 10; P = 0.069). Conclusion We propose a treatment plan for neck disease that involves observing the neck closely following CRT. ND should be planned only when there is evidence that neck disease exists.     

Application of single-cell RNA sequencing in head and neck squamous cell carcinoma

Single-cell RNA sequencing has been broadly applied to head and neck squamous cell carcinoma(HNSCC) for characterizing the heterogeneity and genomic mutations of HNSCC benefiting from the advantage of single-cell resolution. We summarized most of the current studies and aimed to explore their research methods and ideas, as well as how to transform them into clinical applications. Through single-cell RNA sequencing, we found the differences in tumor cells’ expression programs and differentiation ...     

Treatment of recurrent head and neck cancer: re-irradiation or chemotherapy?

For most patients with head and neck cancer, locoregional disease recurrence carries an extremely poor prognosis and has severe adverse effects on quality of life. Only a few patients are suitable for salvage surgery and, even in selected cases, the success rate is low. Most patients are managed by supportive palliative care, or with palliative chemotherapy. In the UK, re-irradiation is rarely used because of concerns about treatment-related toxicity and lack of efficacy. Despite this, a significant body of evidence suggests that re-irradiation may have a higher probability of achieving local control than other treatments. In this review, we discuss the use of re-irradiation in patients with locally recurrent head and neck cancer, and present the pertinent data.     

Is EGFR really a therapeutic target in head and neck cancers?

Epidermal growth factor receptor (EGFR) is overexpressed in 90% to 100% of squamous cell carcinoma of the head and neck (SCCHN). The overexpression of EGFR and its ligand transforming growth factor is associated with poorer survival. EGFR inhibitors such as Cetuximab (Erbitux) have shown a significant antitumoral effect in SCCHN and has improved locoregional control and as well as survival. Even though there was some success with Cetuximab, work with other EGFR inhibition has not been very fruitful and not really shown any promise. Mechanism of action of Cetuximab could be immune-mediated rather than EGFR inhibition and EGFR may not necessarily be a therapeutic target in SCCHN.     

Association of α1 acidic glycoprotein and squamous cell carcinoma of the head and neck

Serum from patients with different malignancies contain an abnormal concentration of a a1-acidic-glycoprotein (AAG) and also, increased levels of AAG are associated with the presence of tumor mass. In the present report, serum levels of AAG were measured by radial immunodiffusion in squamous cell carcinoma of the head and neck (SCCHN) patients taking into account disease status parameters such as tumor localization, stage and extension of disease. Immunohistochemical methods, SDS-PAGE and Western-blotting were employed to study the expression of AAG and a carbohydrate related antigen (sialyl Lewis x) in tumor tissues and derived fractions. AAG showed abnormal levels in 7/15 oral cavity tumor patients sera, 2/5 oropharynx and 5/10 larynx tumors; increased AAG serum levels belonged to patients with disseminated disease. On the other hand, the presence of AAG and sialyl Lewis x were demonstrated in carcinoma cells and in derived fractions from tumor tissues belonging to patients with elevated AAG serum levels. In the present study, we have found elevated levels of AAG in serum samples from SCCHN patients; these neoplastic cells are capable to express AAG.     

Collagen type XI α1 facilitates head and neck squamous cell cancer growth and invasion

Background:

Although it is well established that the extracellular matrix affects tumour progression, not much is known about the various components and their effect on head and neck squamous cell carcinoma (HNSCC) progression. Levels of collagen type XI α1 (colXIα1), a minor fibrillar collagen, have been shown to be increased in tumour compared with normal tissue in several cancers, including colorectal, breast, and non-small cell lung cancer. Currently, the functional significance of colXIα1 is not understood.

Methods:

We examined the expression levels of colXIα1 mRNA and elucidated the functional role of colXIα1 in HNSCC. Cell proliferation, invasion, and migration were examined with and without colXIα1 knockdown with siRNA in HNSCC cells.

Results:

Our data demonstrate that colXIα1 expression is increased in tumour samples compared with levels in normal adjacent tissue in 16/23 HNSCC patients. In addition, colα11 is increased in HNSCC cell lines compared with normal immortalised epithelial cells and is increased in tumour-derived fibroblasts compared with normal fibroblasts. Using an siRNA approach, we demonstrate that colXIα1 contributes to proliferation, migration, and invasion of HNSCC.

Conclusion:

Our cumulative findings suggest that colXIα1 contributes to HNSCC tumorigenesis and may serve as a potential therapeutic target.     

Chemokines and squamous cancer of the head and neck: targets for therapeutic intervention?

The biological properties of squamous carcinoma cells are intimately regulated by a multitude of cytokines and growth factors; the most well studied of these include epidermal growth factor receptor agonists and members of the transforming growth factor-beta family. The recent explosion of research in the field of chemokine function as a mediator of tumor progression has led to the possibility that these small, immunomodulatory proteins also play key roles in squamous carcinogenesis and may, therefore, be potential targets for novel therapeutic approaches.     

Restricting carbohydrates to fight head and neck cancer—is this realistic?

Head and neck cancers (HNCs) are aggressive tumors that typically demonstrate a high glycolytic rate, which results in resistance to cytotoxic therapy and poor prognosis. Due to their location these tumors specifically impair food intake and quality of life, so that prevention of weight loss through nutrition support becomes an important treatment goal. Dietary restriction of carbohydrates (CHOs) and their replacement with fat, mostly in form of a ketogenic diet (KD), have been suggested to accommodate for both the altered tumor cell metabolism and cancer-associated weight loss. In this review, I present three specific rationales for CHO restriction and nutritional ketosis as supportive treatment options for the HNC patient. These are (1) targeting the origin and specific aspects of tumor glycolysis; (2) protecting normal tissue from but sensitizing tumor tissue to radiation- and chemotherapy induced cell kill; (3) supporting body and muscle mass maintenance. While most of these benefits of CHO restriction apply to cancer in general, specific aspects of implementation are discussed in relation to HNC patients. While CHO restriction seems feasible in HNC patients the available evidence indicates that its role may extend beyond fighting malnutrition to fighting HNC itself.KEYWORDS : Ketogenic diet (KD), head and neck neoplasms, diet, carbohydrate restricted (CHO restricted), nutritional support     

Neoadjuvant chemotherapy in head and neck cancer: should it be revisited?

Locally advanced SCCHN (LA-SCCHN) is generally treated by a combination of chemotherapy, irradiation and/or surgery. Timing of the chemotherapy has for long been a matter of debate but concurrent chemoradiation was widely adopted as standard of care for locally advanced squamous cell carcinoma of the head and neck after the publication of a large meta-analysis which demonstrated that concurrent chemoradiation confers an absolute survival benefit of 8% at 2 and 5 years. Induction chemotherapy has some appealing advantages including the opportunity of assessing tumor response and selecting the patients who are candidates for organ preservation. The cisplatin-fluorouracil combination has been the induction regimen of choice for two decades but has recently been superseded by a combination of cisplatin, fluorouracil and a taxane which can be considered the standard regimen when induction chemotherapy is appropriate. Multiple large randomized trials designed to compare sequential induction, i.e., chemotherapy followed by CRT to CRT alone are currently underway. New challenges are the integration of targeted therapies into the current treatment strategies and the identification of prognostic biomarkers and of factors predicting the response to treatment which would help to select patients who are likely to benefit most from induction chemotherapy.