Tumor-associated fatigue develops independently of inflammation

Abstract

Purpose Fatigue is a frequent side effect of cancer and cancer treatment, common to multiple tumor sites and therapeutic strategies. The propagation of peripheral inflammation into the brain is thought to mediate this response. The purpose of this study was to evaluate the role of inflammatory signaling in mediating fatigue induced by multiple syngeneic tumors. Materials/Methods WT, IL-1RIKO, and MyD88 were injected in the flank with HPV+ (mEER), HPV- head and neck cancer, Lewis lung carcinoma (LLC), and two ovarian tumors. Fatigue was measured using wheel running and locomotor activity. Cytokine expression was assessed in the brain, liver, serum, and tumor using qRT-PCR or immunoassay. ANOVA with post hoc Dunnett’s test were used for statistical comparisons with significance set at p Results Wheel running decreased in mEER animals beginning after 10 days and continuing until termination. Inflammatory cytokine expression was seen in the brains, livers, and serum of mEER animals 4 weeks after tumor implantation, but not sooner. IL-1RIKO and MyD88 mice exhibited decreased inflammatory cytokine expression and serum corticosterone, but wheel running and locomotor activity deficits were preserved. Additional tumors induced similar decreases in wheel running, despite varying systemic or brain inflammation. Conclusions Inflammation is sufficient, but not necessary for fatigue-like behavior in tumor bearing mice. Together, these data definitively dissociate fatigue from inflammation and suggest an alternative non-inflammatory mechanism likely underlies most cancer-related fatigue.