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Tumor necrosis factor alpha secreted from oral squamous cell carcinoma contributes to cancer pain and associated inflammation

Scheff, Nicole N.a; Ye, Yia; Bhattacharya, Aditia; MacRae, Justinb; Hickman, Dustin N.b; Sharma, Atul K.b; Dolan, John C.a; Schmidt, Brian L.a,*

doi: 10.1097/j.pain.0000000000001044
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Patients with oral cancer report severe pain during function. Inflammation plays a role in the oral cancer microenvironment; however, the role of immune cells and associated secretion of inflammatory mediators in oral cancer pain has not been well defined. In this study, we used 2 oral cancer mouse models: a cell line supernatant injection model and the 4-nitroquinoline-1-oxide (4NQO) chemical carcinogenesis model. We used the 2 models to study changes in immune cell infiltrate and orofacial nociception associated with oral squamous cell carcinoma (oSCC). Oral cancer cell line supernatant inoculation and 4NQO-induced oSCC resulted in functional allodynia and neuronal sensitization of trigeminal tongue afferent neurons. Although the infiltration of immune cells is a prominent component of both oral cancer models, our use of immune-deficient mice demonstrated that oral cancer–induced nociception was not dependent on the inflammatory component. Furthermore, the inflammatory cytokine, tumor necrosis factor alpha (TNFα), was identified in high concentration in oral cancer cell line supernatant and in the tongue tissue of 4NQO-treated mice with oSCC. Inhibition of TNFα signaling abolished oral cancer cell line supernatant-evoked functional allodynia and disrupted T-cell infiltration. With these data, we identified TNFα as a prominent mediator in oral cancer–induced nociception and inflammation, highlighting the need for further investigation in neural–immune communication in cancer pain.

Two oral cancer pain models were used to demonstrate that cancer-secreted tumor necrosis factor alpha drives nociceptive behavior and T-cell infiltration into the microenvironment.

aBluestone Center for Clinical Research, New York University, New York, NY, USA

bCollege of Dentistry, New York University, New York, NY, USA

Corresponding author. Address: Bluestone Center for Clinical Research, 2nd Floor, 421 1st Ave, New York, NY 10010, USA. Tel.: 212-998-9543. E-mail address: brianl.schmidt@nyu.edu (B.L. Schmidt).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received June 19, 2017

Received in revised form July 25, 2017

Accepted August 03, 2017

© 2017 International Association for the Study of Pain
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