Tumor-associated fatigue in cancer patients develops independently of il1 signaling

Aaron Grossberg, Elisabeth G. Vichaya, Diana L. Christian, Jessica M. Molkentine, Daniel W. Vermeer, Phillip S. Gross, Paola D. Vermeer, John H. Lee, Robert Dantzer

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Fatigue is the most common symptom of cancer at diagnosis, yet causes and effective treatments remain elusive. As tumors can be highly inflammatory, it is generally accepted that inflammation mediates cancer-related fatigue. However, evidence to support this assertion is mostly correlational. In this study, we directly tested the hypothesis that fatigue results from propagation of tumor-induced inflammation to the brain and activation of the central proinflam-matory cytokine, IL1. The heterotopic syngeneic murine head and neck cancer model (mEER) caused systemic inflammation and increased expression of Il1b in the brain while inducing fatigue-like behaviors characterized by decreased voluntary wheel running and exploratory activity. Expression of Il1b in the brain was not associated with any alterations in motivation, measured by responding in a progressive ratio schedule of food reinforcement, depression-like behaviors, or energy balance. Decreased wheel running occurred prior to Il1b detection in the brain, when systemic inflammation was minimal. Furthermore, mice null for two components of IL1b signaling, the type 1 IL1 receptor or the receptor adapter protein MyD88, were not protected from tumor-induced decreases in wheel running, despite attenuated cytokine action and expression. Behavioral and inflammatory analysis of four additional syngeneic tumor models revealed that tumors can induce fatigue regardless of their systemic or central nervous system inflammatory potential. Together, our results show that brain IL1 signaling is not necessary for tumor-related fatigue, dissociating this type of cancer sequela from systemic cytokine expression. Significance: These findings challenge the current understanding of fatigue in cancer patients, the most common and debilitating sequela associated with malignancy.

Original languageEnglish (US)
Pages (from-to)695-705
Number of pages11
JournalCancer Research
Volume78
Issue number3
DOIs
StatePublished - Feb 1 2018
Externally publishedYes

Fingerprint

Fatigue
Neoplasms
Running
Brain
Cytokines
Inflammation
Myeloid Differentiation Factor 88
Reinforcement Schedule
Interleukin-1 Receptors
Encephalitis
Head and Neck Neoplasms
Motivation
Central Nervous System
Depression
Food

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Grossberg, A., Vichaya, E. G., Christian, D. L., Molkentine, J. M., Vermeer, D. W., Gross, P. S., ... Dantzer, R. (2018). Tumor-associated fatigue in cancer patients develops independently of il1 signaling. Cancer Research, 78(3), 695-705. https://doi.org/10.1158/0008-5472.CAN-17-2168

Tumor-associated fatigue in cancer patients develops independently of il1 signaling. / Grossberg, Aaron; Vichaya, Elisabeth G.; Christian, Diana L.; Molkentine, Jessica M.; Vermeer, Daniel W.; Gross, Phillip S.; Vermeer, Paola D.; Lee, John H.; Dantzer, Robert.

In: Cancer Research, Vol. 78, No. 3, 01.02.2018, p. 695-705.

Research output: Contribution to journalArticle

Grossberg, A, Vichaya, EG, Christian, DL, Molkentine, JM, Vermeer, DW, Gross, PS, Vermeer, PD, Lee, JH & Dantzer, R 2018, 'Tumor-associated fatigue in cancer patients develops independently of il1 signaling', Cancer Research, vol. 78, no. 3, pp. 695-705. https://doi.org/10.1158/0008-5472.CAN-17-2168
Grossberg, Aaron ; Vichaya, Elisabeth G. ; Christian, Diana L. ; Molkentine, Jessica M. ; Vermeer, Daniel W. ; Gross, Phillip S. ; Vermeer, Paola D. ; Lee, John H. ; Dantzer, Robert. / Tumor-associated fatigue in cancer patients develops independently of il1 signaling. In: Cancer Research. 2018 ; Vol. 78, No. 3. pp. 695-705.
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