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Tumor-Associated Fatigue in Cancer Patients Develops Independently of IL1 Signaling.

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 proinflammatory 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 IL1β 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. Cancer Res; 78(3); 695-705. ©2017 AACR.

journal_name

Cancer Res

journal_title

Cancer research

authors

Grossberg AJ,Vichaya EG,Christian DL,Molkentine JM,Vermeer DW,Gross PS,Vermeer PD,Lee JH,Dantzer R

doi

10.1158/0008-5472.CAN-17-2168

subject

Has Abstract

pub_date

2018-02-01 00:00:00

pages

695-705

issue

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-17-2168

journal_volume

pub_type

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Tumor-Associated Fatigue in Cancer Patients Develops Independently of IL1 Signaling.