Abstract
Oral cancer patients report severe function-induced pain; severity is greater in females. We hypothesize that a neutrophil-mediated endogenous analgesic mechanism is responsible for sex differences in nociception secondary to oral squamous cell carcinoma (SCC). Neutrophils isolated from the cancer-induced inflammatory microenvironment contain β-endorphin protein and are identified by the Ly6G+ immune marker. We previously demonstrated that male mice with carcinogen-induced oral SCC exhibit less nociceptive behavior and a higher concentration of neutrophils in the cancer microenvironment compared to female mice with oral SCC. Oral cancer cells secrete granulocyte colony stimulating factor (G-CSF), a growth factor that recruits neutrophils from bone marrow to the cancer microenvironment. We found that recombinant G-CSF (rG-CSF, 5 μg/mouse, intraperitoneal) significantly increased circulating Ly6G+ neutrophils in the blood of male and female mice within 24 h of administration. In an oral cancer supernatant mouse model, rG-CSF treatment increased cancer-recruited Ly6G+ neutrophil infiltration and abolished orofacial nociceptive behavior evoked in response to oral cancer supernatant in both male and female mice. Local naloxone treatment restored the cancer mediator-induced nociceptive behavior. We infer that rG-CSF-induced Ly6G+ neutrophils drive an endogenous analgesic mechanism. We then evaluated the efficacy of chronic rG-CSF administration to attenuate oral cancer-induced nociception using a tongue xenograft cancer model with the HSC-3 human oral cancer cell line. Saline-treated male mice with HSC-3 tumors exhibited less oral cancer-induced nociceptive behavior and had more β-endorphin protein in the cancer microenvironment than saline-treated female mice with HSC-3 tumors. Chronic rG-CSF treatment (2.5 μg/mouse, every 72 h) increased the HSC-3 recruited Ly6G+ neutrophils, increased β-endorphin protein content in the tongue and attenuated nociceptive behavior in female mice with HSC-3 tumors. From these data, we conclude that neutrophil-mediated endogenous opioids warrant further investigation as a potential strategy for oral cancer pain treatment.
Highlights
Oral cancer patients report severe function-induced pain; patients experience impaired speech, swallowing, eating, and drinking (Bjordal et al, 2001) and severity is greater in females
To establish a mouse model that permitted assessment of recombinant G-CSF (rG-CSF)-induced changes in Ly6G+ neutrophil infiltration during oral cancer, male and female mice were treated with rG-CSF to increase the percentage of circulating blood Ly6G+ neutrophils; the number of circulating Ly6G+ neutrophils in the blood was quantified with flow cytometry
Male and female mice treated with 5 μg rG-CSF (i.p.) exhibited significantly more Ly6G+ neutrophils in the blood 24 h after injection compared to mice treated with saline (Unpaired t-test, male: t = 5.368, P = 0.001; female: t = 2.9178, P = 0.022; Figure 1)
Summary
Oral cancer patients report severe function-induced pain; patients experience impaired speech, swallowing, eating, and drinking (Bjordal et al, 2001) and severity is greater in females. Female mice with 4-nitroquinoline-1-oxide (4NQO)-induced oral SCC exhibited more orofacial nociceptive behavior compared to male mice (Scheff et al, 2018). Infiltrating neutrophils contribute to decreased nociceptive behavior in male mice during early 4NQO-induced carcinogenesis through opioid-mediated endogenous anti-nociception (Scheff et al, 2018). Peripheral immune-mediated opioid anti-nociception is restricted to the inflammatory site without side effects in response to opioid receptor activation in the central nervous system (Kapitzke et al, 2005). We hypothesize that neutrophil recruitment could be exploited as a therapeutic approach to alleviate oral cancer pain in female mice
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