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(S033) Questioning the Role of Inflammation in Tumor-Induced Fatigue

2017; Elsevier BV; Volume: 98; Issue: 2 Linguagem: Inglês

10.1016/j.ijrobp.2017.02.069

1879-355X

Aaron J. Grossberg, Elisabeth G. Vichaya, Diana L. Christian, Jessica M. Molkentine, Cobi J. Heijnen, Annemieke Kavelaars, Daniel W. Vermeer, John H. Lee, Robert Dantzer,

Fibromyalgia and Chronic Fatigue Syndrome Research

Fatigue is a frequent side effect of cancer and cancer treatment, common to multiple tumor sites and therapeutic strategies. The propagation of inflammation into the brain is thought to mediate this response, based on data evaluating the behavioral response to acute immunologic challenge. This mechanism has not been conclusively linked to cancer-induced fatigue. The purpose of this study was to evaluate the role of inflammatory signaling in mediating fatigue induced by multiple syngeneic tumors. Wild type, IL-1RIKO, and MyD88 adult male mice were individually housed with running wheels. Mice (n=5-9/group) were injected in the flank with murine HPV+ head and neck cancer (mEER). Additional syngeneic tumor lines: HPV- head and neck cancer, Lewis lung carcinoma (LLC), and two ovarian tumors were used to confirm observations. Fatigue was measured using wheel running and locomotor activity. At sacrifice, serum, brains, livers, and tumors were collected. Cytokine expression was assessed in tissue using qRT-PCR or immunoassay. One- or two-way ANOVA with post-hoc Dunnett's test were used for statistical comparisons with significance set at p<.05. Wheel running decreased in mEER animals beginning after 10 days and continuing until termination. Inflammatory cytokine expression was seen in the brains (IL-1β), livers (IL-1β, TNF, and IL-6) and serum (IL-6) of mEER animals after 4 weeks. Earlier time points revealed activity deficits prior to any detectable inflammation. Transgenic IL-1RIKO and MyD88 mice exhibited decreased inflammatory cytokine expression and serum corticosterone, but wheel running and locomotor activity deficits were preserved. All four additional tumor lines induced similar decreases in wheel running, however only the LLC stimulated systemic or brain inflammation. Inflammation is sufficient, but not necessary for cancer-related fatigue-like behavior. Together, these data definitively dissociate fatigue from inflammation and suggest an alternative non-inflammatory mechanism likely underlies most cancer-related fatigue.