Granulocyte-Colony Stimulating Factor-Induced Neutrophil Recruitment Provides Opioid-Mediated Endogenous Anti-nociception in Female Mice With Oral Squamous Cell Carcinoma

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.

Knockdown of GSG2 inhibits prostate cancer progression in�vitro and in�vivo

“…Female BALB/c nude mice (4-week old) were purchased from Shanghai SLAC Laboratory Animal Co. Ltd. and divided into two groups randomly (n=6 mice/group). All mice were housed under standard housing conditions as previously described (19).…”

Reactive Oxygen Species: Beyond Their Reactive Behavior

“…The brain and, more specifically, neurons are susceptible to oxidative damage because of the high content of lipids and the heavy oxidative metabolism on which they rely [ 66 ]. Oxidative damages, through an accumulation of misfolded proteins and loss of antioxidant defenses, have been associated with the aging-mediated loss of functions [ 67 ] and neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [ 68 ].…”

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

“…Six to eight-week-old female athymic NU/J ( Foxn1 nu ) nude mice, BALB/cJ mice, and C57BL/6 mice were purchased from The Jackson Laboratory. Female mice were used as they exhibit stronger pain phenotype 62 , 63 and male mice occasionally exhibit aggressive behaviors that require individual housing. Animal experiments were approved by the New York University Institutional Animal Care and Use Committee (IACUC) and performed in accordance with National Institutes of Health guide for the care and use of laboratory animals and the ARRIVE guidelines.…”