Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.

Oral cavity carcinoma (OCC) remains a major cause of morbidity and mortality in patients with head and neck cancer. Although the incidence has decreased over the last decade, outcomes remain stagnant with only a 5% improvement in overall survival in the last 20 years. Although surgical resection remains the primary treatment modality, several areas of controversy exist with regard to work-up, management of the primary and neck tumors, and adjuvant therapy. As surgical techniques evolve, so has the delivery of radiotherapy and systemic treatment, which have helped to improve the outcomes for patients with advanced disease. Recently, the addition of cetuximab has shown promise as a way to improve outcomes while minimizing toxicity, and this remains an active area of study in the adjuvant setting. Advances in microvascular free-flap reconstruction have extended the limits of resection and enabled enhanced restoration of function and cosmesis. While these advances have led to limited survival benefit, evaluation of alternative modalities has gained interest on the basis of success in other head and neck subsites. Organ preservation with definitive chemoradiotherapy, though proven in the larynx and pharynx, remains controversial in OCC. Likewise, although the association of human papillomavirus is well established in oropharyngeal carcinoma, it has not been proven in the pathogenesis or survival of OCC. Future study of the molecular biology and pathogenesis of OCC should offer additional insight into screening, treatment selection, and novel therapeutic approaches.

In this review, we highlight recent discoveries regarding mechanisms contributing to nerve-cancer cross-talk and the effects of nerve-cancer cross-talk on tumor progression and dissemination. High intratumoral nerve density correlates with poor prognosis and high recurrence across multiple solid tumor types. Recent research has shown that cancer cells express neurotrophic markers such as nerve growth factor, brain-derived neurotrophic factor, and glial cell–derived neurotrophic factor and release axon-guidance molecules such as ephrin B1 to promote axonogenesis. Tumor cells recruit new neural progenitors to the tumor milieu and facilitate their maturation into adrenergic infiltrating nerves. Tumors also rewire established nerves to adrenergic phenotypes via exosome-induced neural reprogramming by p53-deficient tumors. In turn, infiltrating sympathetic nerves facilitate cancer progression. Intratumoral adrenergic nerves release noradrenaline to stimulate angiogenesis via VEGF signaling and enhance the rate of tumor growth. Intratumoral parasympathetic nerves may have a dichotomous role in cancer progression and may induce Wnt–β-catenin signals that expand cancer stem cells. Importantly, infiltrating nerves not only influence the tumor cells themselves but also impact other cells of the tumor stroma. This leads to enhanced sympathetic signaling and glucocorticoid production, which influences neutrophil and macrophage differentiation, lymphocyte phenotype, and potentially lymphocyte function. Although much remains unexplored within this field, fundamental discoveries underscore the importance of nerve-cancer cross-talk to tumor progression and may provide the foundation for developing effective targets for the inhibition of tumor-induced neurogenesis and tumor progression.