Defining TRPV4 Contribution of Schwann Cells to Oral Cancer Pain

Oral cancer, particularly squamous cell carcinoma (SCC), represents nearly 90% of all head and neck cancers. Most patients with oral cancer experience functional pain caused by pressure at the cancer site, along with discomfort from stretching during activities like talking, drinking, and swallowing. However, the intensity and nature of this pain can vary significantly among individual patients. Currently, there are no effective treatments available to relieve pain associated with oral cancer. The current hypothesis regarding the cause of oral cancer pain suggests that oral cancers release pain mediators that sensitize and activate receptors on sensory nerves associated with cancer. Mechanosensitive ion channels, such as TRPV4, PIEZO1, and PIEZO2, are activated by pressure and stretch, and have been implicated in pathological pain. Preclinical studies show that mice lacking TRPV4 have impaired pressure sensation, and inhibiting TRPV4 in models of oral cancer reduces mechanical pain. TRPV4 is expressed in various cell types, including epithelial cells, fibroblasts, neurons, and Schwann cells, which are the glial cells that ensheathe the axons of sensory neurons. Cancer cells and Schwann cells interact reciprocally, promoting cancer growth and pain. Preliminary data indicate that Schwann cells isolated from the trigeminal nerve fibers innervating the cancers of oral cancer patients express functional TRPV4. In human Schwann cells, the activation of TRPV4 mediates mechanosensitivity. A TRPV4 inhibitor currently in clinical trials has been well-tolerated by patients and has demonstrated a good safety profile. A better understanding of TRPV4's role in oral cancer pain holds significant promise for the development of TRPV4 antagonists as new analgesics for alleviating pain in oral cancer patients. There is a lack of published data regarding the effects of pressure and stretch on pain phenotypes in patients with oral cancers. This gap significantly hinders our understanding of the mechanisms underlying oral cancer pain. By quantitatively assessing the pressure and stretch sensitivities experienced by these patients, the investigators can gain valuable insights into the origins of their pain. In this proposal, the investigators hypothesize that the quality of pain experienced by oral cancer patients is influenced by the activation levels of mechanosensitive ion channels at the site of the cancer. The investigators will conduct sensitivity tests for pressure and stretch on oral cancer patients and compare the patients' sensitivities with those of healthy subjects. Furthermore, the investigators will evaluate the correlation between pressure and stretch sensitivity scores in oral cancer patients. The investigators propose that the degree of pressure and stretch sensitivities experienced by oral cancer patients is quantifiable and depends on the functional expression of TRPV4 on Schwann cells.