Advances in Head and Neck Cancer Pain.

Head and neck cancer (HNC) affects over 890,000 people annually worldwide and has a mortality rate of 50%. Aside from poor survival, HNC pain impairs eating, drinking, and talking in patients, severely reducing quality of life. Different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between cancers. Poor pathologic features (e.g., perineural invasion, lymph node metastasis) are associated with increased pain. The use of syngeneic/immunocompetent animal models, as well as a new mouse model of perineural invasion, provides novel insights into the pathobiology of HNC pain. Glial and immune modulation of the tumor microenvironment affect not only cancer progression but also pain signaling. For example, Schwann cells promote cancer cell proliferation, migration, and secretion of nociceptive mediators, whereas neutrophils are implicated in sex differences in pain in animal models of HNC. Emerging evidence supports the existence of a functional loop of cross-activation between the tumor microenvironment and peripheral nerves, mediated by a molecular exchange of bioactive contents (pronociceptive and protumorigenic) via paracrine and autocrine signaling. Brain-derived neurotrophic factor, tumor necrosis factor α, legumain, cathepsin S, and A disintegrin and metalloprotease 17 expressed in the HNC microenvironment have recently been shown to promote HNC pain, further highlighting the importance of proinflammatory cytokines, neurotrophic factors, and proteases in mediating HNC-associated pain. Pronociceptive mediators, together with nerve injury, cause nociceptor hypersensitivity. Oncogenic, pronociceptive mediators packaged in cancer cell-derived exosomes also induce nociception in mice. In addition to increased production of pronociceptive mediators, HNC is accompanied by a dampened endogenous antinociception system (e.g., downregulation of resolvins and µ-opioid receptor expression). Resolvin treatment or gene delivery of µ-opioid receptors provides pain relief in preclinical HNC models. Collectively, recent studies suggest that pain and HNC progression share converging mechanisms that can be targeted for cancer treatment and pain management.

DNA promoter hypermethylation in saliva for the early diagnosis of oral cancer.

Oral health care professionals could drastically improve the quality of life for patients with potentially malignant oral lesions by using a noninvasive test that could be used to detect cancer using saliva. Promoter DNA hypermethylation is a critical step in oral carcinogenesis and has a number of significant advantages over genetic and protein diagnostic markers. Methylight is a recently developed assay that rapidly quantifies promoter hypermethylation and could potentially be applied into a clinical setting.

RAF Kinase Inhibitory Protein Expression and Phosphorylation Profiles in Oral Cancers.

Raf Kinase Inhibitory Protein (RKIP) expression has been profiled for a number of unique tissue cancers. However, certain tissues have not been explored, and oral and oropharyngeal cancers stand out as high priority targets, given their relatively high incidence, high morbidity rate, and in many cases, preventable nature. The purpose of this study was to examine changes in RKIP expression and phosphorylation in tissues resected from oral cancer patients, and compare to results generated from immortalized cell lines raised from primary oral cancer tissues, including oral squamous cell carcinoma line 4 (SCC4) and human squamous cell carcinoma line 3 (HSC3). Out of 4 human samples collected from male and female patients across various ages with variable risk factors, we observed an across the board reduction in RKIP expression. Two human samples demonstrated a significant increase in phosphorylated RKIP when normalized to total RKIP, however all 4 were increased when normalized to total cellular protein. The immortalized oral cancer cell culture HSC3 revealed significant increases in phosphorylated RKIP with no change in total RKIP expression, while line SCC4 demonstrated an increase in both total and phosphorylated RKIP. Results presented here indicate that oral cancers behave similarly to other cancers in terms of changes in RKIP expression and phosphorylation, although immortalized cell line expression profiles significantly differ from human tissue biopsies.

Review of preclinical studies on treatment of mucositis and associated pain.

Oral mucositis is a significant problem in cancer patients treated with radiation or chemotherapy, often hindering definitive cancer treatment. For patients with oral mucositis, pain is the most distressing symptom, leading to loss of orofacial function and poor quality of life. While oral mucositis has been well-described, its pathophysiology is poorly understood. Oral health professionals treating patients with mucositis have almost no effective therapies to treat or prevent oral mucositis. The purpose of this review is to (1) describe the current preclinical models of oral mucositis and their contribution to the understanding of mucositis pathophysiology, (2) explore preclinical studies on therapies targeting mucositis and discuss the clinical trials that have resulted from these preclinical studies, and (3) describe the proposed pathophysiology of oral mucositis pain and preclinical modeling of oral mucositis pain.

Biologic mechanisms of oral cancer pain and implications for clinical therapy.

Cancer pain is an ever-present public health concern. With innovations in treatment, cancer patients are surviving longer, but uncontrollable pain creates a poor quality of life for these patients. Oral cancer is unique in that it causes intense pain at the primary site and significantly impairs speech, swallowing, and masticatory functions. We propose that oral cancer pain has underlying biologic mechanisms that are generated within the cancer microenvironment. A comprehensive understanding of key mediators that control cross-talk between the cancer and peripheral nervous system, and possible interventions, underlies effective cancer pain management. The purpose of this review is to explore the current studies on oral cancer pain and their implications in clinical management for cancer pain in general. Furthermore, we will explore the endogenous opioid systems and novel cancer pain therapeutics that target these systems, which could solve the issue of opiate tolerance and improve quality of life in oral cancer patients.