Tnf Alpha Promotes Oral Cancer Growth, Pain, And Schwann Cell Activation

Oral cancer is very painful and impairs a patient's ability to eat, talk, and drink. Mediators secreted from oral cancer can excite and sensitize sensory neurons inducing pain. Cancer mediators can also activate Schwann cells, the peripheral glia that regulates neuronal function and repair. The contribution of Schwann cells to oral cancer pain is unclear. We hypothesize that the oral cancer mediator TNF alpha activates Schwann cells, which further promotes cancer progression and pain. We demonstrate that TNF alpha is overexpressed in human oral cancer tissues and correlates with increased self-reported pain in patients. Antagonizing TNF alpha reduces oral cancer proliferation, cytokine production, and nociception in mice with oral cancer. Oral cancer or TNF alpha alone increases Schwann cell activation (measured by Schwann cell proliferation, migration, and activation markers), which can be inhibited by neutralizing TNF alpha. Cancer- or TNF alpha -activated Schwann cells release pro-nociceptive mediators such as TNF alpha and nerve growth factor (NGF). Activated Schwann cells induce nociceptive behaviors in mice, which is alleviated by blocking TNF alpha. Our study suggests that TNF alpha promotes cancer proliferation, progression, and nociception at least partially by activating Schwann cells. Inhibiting TNF alpha or Schwann cell activation might serve as therapeutic approaches for the treatment of oral cancer and associated pain.