Fragmented Sleep Accelerates Tumor Growth and Progression through Recruitment of Tumor-Associated Macrophages and TLR4 Signaling
Open accessAbstract
Sleep fragmentation (SF) is a highly prevalent condition and a hallmark of sleep apnea, a condition that has been associated with increased cancer incidence and mortality. In this study, we examined the hypothesis that sleep fragmentation promotes tumor growth and progression through proinflammatory TLR4 signaling. In the design, we compared mice that were exposed to sleep fragmentation one week before engraftment of syngeneic TC1 or LL3 tumor cells and tumor analysis four weeks later. We also compared host contributions through the use of mice genetically deficient in TLR4 or its effector molecules MYD88 or TRIF. We found that sleep fragmentation enhanced tumor size and weight compared with control mice. Increased invasiveness was apparent in sleep fragmentation tumors, which penetrated the tumor capsule into surrounding tissues, including adjacent muscle. Tumor-associated macrophages (TAM) were more numerous in sleep fragmentation tumors, where they were distributed in a relatively closer proximity to the tumor capsule compared with control mice. Although tumors were generally smaller in both MYD88−/− and TRIF−/− hosts, the more aggressive features produced by sleep fragmentation persisted. In contrast, these more aggressive features produced by sleep fragmentation were abolished completely in TLR4−/− mice. Our findings offer mechanistic insights into how sleep perturbations can accelerate tumor growth and invasiveness through TAM recruitment and TLR4 signaling pathways. Cancer Res; 74(5); 1329–37. ©2014 AACR.
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The link between sleep disturbances and immune measures has been investigated in depression, schizophrenia, alcohol dependence, hemodialysis, organ transplantation, pregnancy, cervical cancer risk, and diabetes, with most studies reporting a significant association between some aspects of sleep disturbances and immune measures.
“The link between sleep disturbances and immune measures has been also investigated in depression (124, 227, 393, 532), schizophrenia (176), alcohol dependence (462), hemodialysis (107, 458), organ transplantation (193), pregnancy (55, 409), cervical cancer risk (491), and diabetes (548), with most studies reporting a significant association between some aspects of sleep disturbances and immune mea”
From The Sleep-Immune Crosstalk in Health and Disease (2019) · cites this paper as [227]
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- Authors
- Hakim, F., Wang, Y., Zhang, S. X. L., Zheng, J., Yolcu, E. S., Carreras, A., Khalyfa, A., Shirwan, H., Almendros, I., & Gozal, D.
- Affiliations
- University of Louisville (US)
- Corresponding author
- Gozal, David
- ORCID
- Venue
- Cancer Research
- Published
- 2014-03-01
- Volume
- 74
- Issue
- 5
- Pages
- 1329-1337
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4247537
- OpenAlex
- W2117098447
- Cited by
- 206
- References
- 48
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 25 · 2023: 16 · 2022: 23 · 2021: 14 · 2020: 18 · 2019: 16 · 2018: 13 · 2017: 12 · 2016: 22 · 2015: 21 · 2014: 6
- FWCI
- 15.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL086662, HL086662, HL065270, R01HL065270)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Keywords
- sleep fragmentation, sleep apnea, tumor growth, tumor progression, tumor-associated macrophages, TLR4 signaling, MyD88, TRIF, tumor invasion, pro-inflammatory signaling, host immune response to cancer
- MeSH terms
- Animals, Macrophages, Male, Mice, Inbred C57BL, Neoplasms, Sleep Deprivation, Signal Transduction, Disease Progression, Adaptor Proteins, Vesicular Transport, Toll-Like Receptor 4, Mice, Myeloid Differentiation Factor 88
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