TNFα promotes oral cancer growth, pain, and Schwann cell activation

Abstract

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.

Tumor-Induced Inflammatory Cytokines and the Emerging Diagnostic Devices for Cancer Detection and Prognosis

“…In the ovarian organoid model, prolonged TNF exposure confers precancerous phenotypes with high expression of cancer markers (43). TNF also induces the formation of cancer stem-like phenotypes in oral squamous cell carcinoma (44,45). Furthermore, TNF can directly stimulate breast cancer proliferation via the positive feedback loop of TNFR-1/NF-kB/STAT-3 (46) as well as be involved in cathepsin C-induced hepatocellular malignancy via MAPK signaling pathway (47).…”

Schwann Cells in Digestive System Disorders

“…Glia are recognised as mediators of orofacial pain [ 91 , 92 ], and several studies suggest that SCs are involved in the increased nociception [ 58 , 59 ] and nerve invasion [ 60 , 61 ] observed in oral malignancies. One of the proposed mechanisms is the activation of SCs in response to tumour necrosis factor alpha (TNFα) secreted by OSCC cells.…”

“…This activation, in turn, stimulates TNFα and nerve growth factor (NGF) production by SCs themselves. TNFα overexpression is found in oral cancer tissues and is indeed correlated with elevated pain, while supernatants from activated SCs can increase facial allodynia in mice [ 59 ]. The TrkB/BDNF signalling axis is involved in the oral cancer PNI process, since modulation of this pathway in co-culture studies regulates SC—tumour cell interaction, and influences cell migration and differentiation [ 60 , 61 ].…”

Glia and Orofacial Pain: Progress and Future Directions

“…Schwann cells are activated in the presence of pancreatic, colon, gastric, lung, skin, and oral cancer cells and promote cancer growth, invasion, and dispersion [11,52,[140][141][142][143][144][145][146][147][148][149]. Cancer-activated Schwann cells secrete neurotrophic factors, chemokines/cytokines, proteases, and adhesion molecules [52,143,146,147,149,150], many of which could directly excite and sensitize primary afferent neurons [151][152][153]. We and others recently found that Schwann cells and oral cancer cells reciprocally interact to promote each other's growth, migration, and invasion [52,147,152].…”

“…Cancer-activated Schwann cells secrete neurotrophic factors, chemokines/cytokines, proteases, and adhesion molecules [52,143,146,147,149,150], many of which could directly excite and sensitize primary afferent neurons [151][152][153]. We and others recently found that Schwann cells and oral cancer cells reciprocally interact to promote each other's growth, migration, and invasion [52,147,152]. Besides, supernatant collected from oral cancer-activated Schwann cells produces a nociceptive response in mice [52].…”