TNF\u03b1 promotes oral cancer growth, pain, and Schwann cell activation

Elizabeth Salvo,Nguyen H Tu,Zinaida A Dubeykovskaya,Yi Ye,Bradley E Aouizerat,Nicole N Scheff,Shruti A Chavan

doi:10.1038/s41598-021-81500-4

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.

Highlights

Oral cancer is very painful and impairs a patient’s ability to eat, talk, and drink
We found that TNFα is secreted from oral cancer cell lines and upregulated in cancer tongue tissues collected from mice treated with the carcinogen 4-nitroquinoline 1-oxide (4NQO)[9]
Using hematoxylin and eosin (H&E) stained sections of the paw, we found that the percentage of tumor area relative to the total paw area was smaller in C-87 treated mice than the vehicle control (P < 0.01, Fig. 3c,d)

Summary

Introduction

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- or TNFα-activated Schwann cells release pro-nociceptive mediators such as TNFα and nerve growth factor (NGF). Oral cancers produce and secrete algogenic mediators that activate and sensitize primary afferent neurons to initiate pain[7,8,9]. One such mediator is TNFα, a “master regulator” cytokine that initiates inflammation and drives pro-inflammatory cytokine cascades[10]. The peripheral glia that ensheathes peripheral nerves, may be a major source for pro-inflammatory mediators that contribute to cancer growth and pain. We examined the effect of TNFα inhibition on cancer growth, Schwann cell activation, and pain-like behaviors using cell culture and animal models of oral cancer

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