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Cancer Res. 2014 Mar 1;74(5):1329-37. doi: 10.1158/0008-5472.CAN-13-3014. Epub 2014 Jan 21.

Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling.

Author information

1
Authors' Affiliations: Pediatric Sleep Medicine, Department of Pediatrics, Comer Children's Hospital, The University of Chicago, Chicago, Illinois; and Department of Microbiology and Immunology, The University of Louisville, Louisville, Kentucky.

Abstract

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.

PMID:
24448240
PMCID:
PMC4247537
DOI:
10.1158/0008-5472.CAN-13-3014
[Indexed for MEDLINE]
Free PMC Article

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