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Tumor-Associated Fatigue in Cancer Patients Develops Independently of Interleukin-1 Signaling

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Tumor-Associated Fatigue in Cancer Patients Develops Independently of Interleukin-1 Signaling Author Manuscript Published OnlineFirst on December 7, 2017; DOI: 10.1158/0008-5472.CAN-17-2168 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Tumor-associated fatigue in cancer patients develops independently of interleukin-1 signaling Aaron J. Grossberg1,2, Elisabeth G. Vichaya2, Diana L. Christian2, Jessica M. Molkentine3, Daniel W. Vermeer4, Phillip S. Gross2, Paola D. Vermeer4, John H. Lee4, Robert Dantzer2 1 Department of Radiation Oncology, MD Anderson Cancer Center, 1400 Pressler St., Unit 1422, Houston, TX 77030, United States 2 Department of Symptom Research, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 384, Houston, TX 77030, United States 3 Department of Experimental Radiation Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 66, Houston, TX 77030, United States 4 Cancer Biology Research Center, Sanford Research, 2301 E. 60th St. N., Sioux Falls, SD 57104, United States Running title: Fatigue and inflammation Corresponding author: Aaron J. Grossberg, Departments of Radiation Oncology and Symptom Research, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1422, Houston, TX 77030. Tel: (832) 750-1557 e-mail: [email protected] Conflicts of interest: RD has received an honorarium from Danone Nutricia Research. The authors declare no other conflicts of interest. Keywords: fatigue, head and neck cancer, interleukin-1, cytokines, behavior 1 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2017; DOI: 10.1158/0008-5472.CAN-17-2168 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 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 pro-inflammatory cytokine, interleukin-1 (IL-1). 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, depressive-like behaviors, or energy balance. Decreased wheel running occurred prior to Il1b detection in the brain, when systemic inflammation was minimal. Further, mice null for two components of IL-1β signaling, the type 1 interleukin- 1 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 4 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 IL-1 signaling is not necessary for tumor-related fatigue, dissociating this type of cancer sequela from systemic cytokine expression. 2 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2017; DOI: 10.1158/0008-5472.CAN-17-2168 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Cancer-related fatigue is among the most common and distressing presenting symptoms of malignancy. Although nearly all patients report fatigue after treatment, various studies report the prevalence of fatigue prior to cancer treatment ranging from 25 to >50% of patients depending on sample and methodology (1). Fatigue strongly impacts quality of life (2) and physical functioning (3), and has been linked to poorer survival in colorectal cancer patients whose fatigue alters daytime activity patterns (4). The search for fatigue-directed treatments has been largely unsuccessful, yielding equivocal results with psychostimulants (5) and only modest benefit with exercise (6), a challenging intervention for severely fatigued patients. Multiple studies have linked cancer-related fatigue to psychosocial factors including pre-existing fatigue, depression, and childhood stress (7). However, fatigue remains prevalent in patients without these risk factors and is observed in animal models of cancer in the form of reduced motor activity (8,9), strongly supporting a conserved biological mechanism for cancer-related fatigue. Multiple biological contributions to cancer-related fatigue have been investigated, including anemia, endocrine dysregulation, and altered metabolism (7). However, much of the attention has focused on the role of inflammatory cytokine signaling in the pathogenesis of fatigue. Studies carried out mainly in rodents injected with endotoxin demonstrate that peripheral inflammatory signals are propagated into the central nervous system, where cytokines act to cause fatigue, anorexia, and depressive-like behaviors (10). Intracerebroventricular administration of cytokines is sufficient to induce these behaviors (11), and blockade of cytokine signaling within the brain can abrogate 3 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2017; DOI: 10.1158/0008-5472.CAN-17-2168 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. fatigue in response to peripherally administered endotoxin (12). Cancer cells can both produce inflammatory cytokines, and induce potent local and systemic inflammatory responses in situ (13). Cancer treatment is also associated with an increase in circulating cytokine levels (14,15). Studies in both humans and rodents demonstrate enhanced cytokine expression in response to various stressors (16,17), mirroring the association between early life stress and fatigue seen in cancer patients. These converging data point to the possibility that fatigue and other behavioral changes caused by cancer are also mediated via propagation of peripheral inflammation into the brain (1,7,10,18). Over the past 15 years, multiple researchers have investigated this connection, with the preponderance of studies focusing on the relationship between inflammation and fatigue during and after cancer therapy (7). Although associations between fatigue and circulating cytokines have been often reported in both the clinical and preclinical settings, data supporting the inflammatory hypothesis of fatigue have been entirely correlational in nature; few published accounts support a causative relationship between inflammatory cytokines and cancer-related fatigue, but they rely on murine models of cancer that quickly progress to cachexia (19,20). In the present study, we used a syngeneic murine model of human papillomavirus-positive head and neck cancer (mEER) (21,22), which reliably induces expression of interleukin-1 beta (Il1b), interleukin-6 (Il6) and tumor necrosis factor (Tnf) in the liver and Il1b in the brain, and reproducible fatigue-like behavior in the absence of anorexia and cachexia, to ask whether activation of IL-1 signaling is a required intermediary of cancer-related fatigue in the pre-treatment setting. Using voluntary wheel running and novel cage exploratory 4 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2017; DOI: 10.1158/0008-5472.CAN-17-2168 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. activity as behavioral measures of fatigue, we evaluated the time course of tumor- induced brain inflammation and tested mice null for the type 1 interleukin-1 receptor (IL- 1R1-/-) and the inflammatory adaptor protein myeloid differentiation primary response gene 88 (MyD88-/-) to assess the possible relationship between fatigue-like behaviors and inflammatory signaling. Methods and Materials Animals Male C57BL/6J wild type (WT), IL-1R1-/- (Stock# 003245), and MyD88-/- (Stock# 009088) mice were purchased from The Jackson Labs (Bar Harbor, ME, USA), and colonies were maintained in our animal facility via pairing of mice homozygous for knockout alleles. All mice were genotyped using standard protocols from The Jackson Labs. Experiments were conducted on 10-13 week old male mice individually housed in temperature and humidity controlled environments on 12 h light–dark cycles. Food and water were available ad libitum unless otherwise specified. All procedures described in this study were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committees of the University of Texas MD Anderson Cancer Center. Tumor Models Adult male C57BL/6J mice (n=5-10/group) were injected with 100 ul of tumor cell suspension into the right flank subcutaneous space. The following heterotopic syngeneic tumor models and inoculation doses were used
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