Bluestone Center for Clinical Research, New York University College of Dentistry, 421 First Avenue, 233W, New York, NY, 10010, USA.
Department of Oral Maxillofacial Surgery, New York University College of Dentistry, New York, USA.
Sci Rep. 2021 Jan 19;11(1):1840. doi: 10.1038/s41598-021-81500-4.
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 TNFα activates Schwann cells, which further promotes cancer progression and pain. We demonstrate that TNFα is overexpressed in human oral cancer tissues and correlates with increased self-reported pain in patients. Antagonizing TNFα reduces oral cancer proliferation, cytokine production, and nociception in mice with oral cancer. Oral cancer or TNFα alone increases Schwann cell activation (measured by Schwann cell proliferation, migration, and activation markers), which can be inhibited by neutralizing TNFα. Cancer- or TNFα-activated Schwann cells release pro-nociceptive mediators such as TNFα and nerve growth factor (NGF). Activated Schwann cells induce nociceptive behaviors in mice, which is alleviated by blocking TNFα. Our study suggests that TNFα promotes cancer proliferation, progression, and nociception at least partially by activating Schwann cells. Inhibiting TNFα or Schwann cell activation might serve as therapeutic approaches for the treatment of oral cancer and associated pain.
口腔癌非常疼痛，会损害患者的进食、说话和饮水能力。口腔癌分泌的介质可以兴奋和敏化感觉神经元，引起疼痛。癌症介质还可以激活施万细胞，即调节神经元功能和修复的周围神经胶质细胞。施万细胞对口腔癌疼痛的贡献尚不清楚。我们假设口腔癌介质 TNFα 会激活施万细胞，从而进一步促进癌症的进展和疼痛。我们证明 TNFα 在人类口腔癌组织中过度表达，并与患者自述疼痛增加相关。拮抗 TNFα 可减少口腔癌小鼠的增殖、细胞因子产生和痛觉过敏。口腔癌或 TNFα 单独增加施万细胞的激活（通过施万细胞增殖、迁移和激活标志物来衡量），而中和 TNFα 可抑制其激活。癌或 TNFα 激活的施万细胞释放促伤害性介质，如 TNFα 和神经生长因子 (NGF)。激活的施万细胞在小鼠中引起伤害性行为，而阻断 TNFα 可减轻这些行为。我们的研究表明，TNFα 通过激活施万细胞促进癌症增殖、进展和痛觉过敏。抑制 TNFα 或施万细胞激活可能是治疗口腔癌和相关疼痛的一种治疗方法。
