Advances in Head and Neck Cancer Pain

Abstract

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.

Head and Neck Cancer-derived small extracellular vesicles sensitize TRPV1+ neurons to mediate cancer pain

“…One reason might be the regulation of tumor immunology by neurons (Scheff et al 2022, Udit et al 2022). Given that pain is a prognostic factor for survival (Reyes-Gibby et al 2014), it suggests shared mechanisms linking carcinogenesis and pain in HNSCC (Ye et al 2022). Our present work shows that sEVs released by cancer cells are a key mediator of communication to TRPV1+ neurons in line with previous reports (Madeo et al 2018, Vermeer 2019, Amit et al 2020).…”

“…Upregulation of ATF3 in neurons following exposure to isolated sEVs further supports this hypothesis. ATF3 is classically upregulated after nerve injury, TRPV1 activation, and is associated with transcriptional reprogramming necessary for peripheral nerve regeneration and neuropathic pain (Tsujino et al 2000, Bráz et al 2010, Renthal et al 2020), suggesting that cancer pain has a neuropathic component (Ye et al 2022). The upregulation of ATF3 in response to sEVs supports the idea that sEVs drastically impact the neuronal gene expression to switch to a transcriptome facilitating axon elongation and neuronal sensitization.…”

“…If no sex difference is observed with male sEVs affecting equally female and male neurons, a difference may emerge between sEV isolated from female and male mice. However, the presence of sexual dimorphism in HNCP is still elusive (Ye et al 2022).…”

Schwann Cells Induce Phenotypic Changes in Oral Cancer Cells

“…[48,50,74] Schwann cells are also involved in cancer pain. [12,16,25,44,45,69,70] In the present study, we hypothesize that SCs can promote oral cancer cell aggressiveness. We quantified OSCC cell proliferation, invasion, morphology, and metabolism in the presence of SCs.…”

“…Since SCs have been implicated in cancer metastasis, [74] and pain, [12,16,25,44,45,69,70] we asked whether there are a set of common cancer genes that regulate both metastasis and pain that could be affected by the presence of SCs. In a recent RNAsequencing study conducted at NYU Oral Cancer Center, a total of 40 upregulated DEGs were found to be associated with both nodal metastasis and pain in oral cancer patients.…”