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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 IL1? 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.

SUBMITTER: Grossberg AJ

PROVIDER: S-EPMC5811314 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Grossberg Aaron J AJ Vichaya Elisabeth G EG Christian Diana L DL Molkentine Jessica M JM Vermeer Daniel W DW Gross Phillip S PS Vermeer Paola D PD Lee John H JH Dantzer Robert R

Cancer research 20171207 3

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 ...[more]

PMID: 29217760

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Project description:BACKGROUND:Hypoxia plays a relevant role in tumor-related inflammation toward the metastatic spread and cancer aggressiveness. The pro-inflammatory cytokine interleukin-1? (IL-?) and its cognate receptor IL1R1 contribute to the initiation and progression of breast cancer determining pro-tumorigenic inflammatory responses. The transcriptional target of the hypoxia inducible factor-1? (HIF-1?) namely the G protein estrogen receptor (GPER) mediates a feedforward loop coupling IL-1? induction by breast cancer-associated fibroblasts (CAFs) to IL1R1 expression by breast cancer cells toward the regulation of target genes and relevant biological responses. METHODS:In order to ascertain the correlation of IL-? with HIF-1? and further hypoxia-related genes in triple-negative breast cancer (TNBC) patients, a bioinformatics analysis was performed using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets. Gene expression correlation, statistical analysis and gene set enrichment analysis (GSEA) were carried out with R studio packages. Pathway enrichment analysis was evaluated with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. TNBC cells and primary CAFs were used as model system. The molecular mechanisms implicated in the regulation of IL-1? by hypoxia toward a metastatic gene expression profile and invasive properties were assessed performing gene and protein expression studies, PCR arrays, gene silencing and immunofluorescence analysis, co-immunoprecipitation and ChiP assays, ELISA, cell spreading, invasion and spheroid formation. RESULTS:We first determined that IL-1? expression correlates with the levels of HIF-1? as well as with a hypoxia-related gene signature in TNBC patients. Next, we demonstrated that hypoxia triggers a functional liaison among HIF-1?, GPER and the IL-1?/IL1R1 signaling toward a metastatic gene signature and a feed-forward loop of IL-1? that leads to proliferative and invasive responses in TNBC cells. Furthermore, we found that the IL-1? released in the conditioned medium of TNBC cells exposed to hypoxic conditions promotes an invasive phenotype of CAFs. CONCLUSIONS:Our data shed new light on the role of hypoxia in the activation of the IL-1?/IL1R1 signaling, which in turn triggers aggressive features in both TNBC cells and CAFs. Hence, our findings provide novel evidence regarding the mechanisms through which the hypoxic tumor microenvironment may contribute to breast cancer progression and suggest further targets useful in more comprehensive therapeutic strategies.

Project description:ImportanceThe association and interaction of host characteristics with prognosis in patients with oral cavity squamous cell carcinoma (OSCC) are poorly understood. There is increasing evidence that host characteristics are associated with treatment outcomes of many cancers.ObjectivesTo examine the host factors associated with prognosis in patients with OSCC and their interactions to create a numerical index that quantifies the prognostic capacity of these host characteristics.Design, setting, and participantsThis retrospective cohort study included patients with OSCC treated surgically at a tertiary care center from January 1, 1998, to December 31, 2015. From a departmental OSCC database of 1377 previously untreated patients, 68 patients with missing data on any host variable of interest within a month before the start of treatment were excluded, leaving 1309 patients. Data analysis was performed from October 21, 2019, to December 10, 2019.ExposurePrimary surgery for OSCC.Main outcomes and measuresOverall survival (OS) was the primary end point, and disease-specific survival (DSS) was the secondary end point. Optimal cutoffs for each variable were identified using recursive-partitioning analysis with the classification and regression tree method using OS as the dependent variable. Body mass index (BMI) and pretreatment peripheral blood leukocyte count, platelet count, hemoglobin level, and albumin level were analyzed. A host index (H-index) was developed using independent factors associated with OS.ResultsA total of 1309 patients (731 [55.8%] male; mean [SD] age, 62 [14.3] years) participated in the study. When including all the host-related factors in a multivariable analysis, all except BMI (hazard ratio [HR], 1.14; 95% CI, 0.80-1.63) were independently associated with outcomes. For example, compared with a hemoglobin level of 14.1 g/dL or greater, the HR for a level of 12.9 to 14.0 g/dL was 1.42 (95% CI, 1.13-1.77) and for a level of 12.8 g/dL or less was 1.51 (95% CI, 1.18-1.94), and compared with an albumin level of 4.3 g/dL or greater, the HR for a level of 3.7 to 4.2 g/dL was 1.18 (95% CI, 0.95-1.45) and for a level of 3.6 g/dL or less was 3.64 (95% CI, 2.37-5.58). An H-index of 1.4 or less was associated with a 74% 5-year OS, an H-index of 1.5 to 3.5 with a 65% 5-year OS, and an H-index of 3.6 or higher with a 38% 5-year OS; for DSS, the 5-year survival was 84%, 80%, and 64%, respectively. Compared with patients with an H-index score of 1.4 or less, patients with H-index scores of 1.5 to 3.5 (hazard ratio, 1.474; 95% CI, 1.208-1.798) and 3.6 or higher (hazard ratio, 3.221; 95% CI, 2.557-4.058) had a higher risk of death.Conclusions and relevanceThe findings suggest that pretreatment values of neutrophils, monocytes, lymphocytes, hemoglobin, and albumin are independently associated with prognosis in patients with OSCC. The interactions between these host factors were incorporated into a novel H-index that quantified the prognostic capacity of host characteristics associated with OSCC.

Dataset Information

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

Publications

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

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