TY - JOUR
T1 - Tumor-associated fatigue in cancer patients develops independently of il1 signaling
AU - Grossberg, Aaron J.
AU - Vichaya, Elisabeth G.
AU - Christian, Diana L.
AU - Molkentine, Jessica M.
AU - Vermeer, Daniel W.
AU - Gross, Phillip S.
AU - Vermeer, Paola D.
AU - Lee, John H.
AU - Dantzer, Robert
N1 - Funding Information:
The authors thank Dr. Steven Lin (MD Anderson Cancer Center, Houston, TX) for providing the LLC cell line and Dr. Anil Sood (MD Anderson Cancer Center, Houston, TX) for providing the ID8 and IG10 cell lines. This work was supported by the National Cancer Institute of the NIH [R01 CA193522, to R. Dantzer]. Additional support came from the University of Texas MD Anderson Cancer Center and the NIH MD Anderson Cancer Center Support Grant (P30 CA016672).
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-17-2168
DO - 10.1158/0008-5472.CAN-17-2168
M3 - Article
C2 - 29217760
AN - SCOPUS:85041452740
SN - 0008-5472
VL - 78
SP - 695
EP - 705
JO - Cancer Research
JF - Cancer Research
IS - 3
ER -