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Original Research: Sleep Disorders |

Tumor Cell Malignant Properties Are Enhanced by Circulating Exosomes in Sleep Apnea

Isaac Almendros, PhD; Abdelnaby Khalyfa, PhD; Wojciech Trzepizur, MD, PhD; Alex Gileles-Hillel, MD; Lei Huang, PhD; Mahzad Akbarpour, PhD; Jorge Andrade, PhD; Ramon Farré, PhD; David Gozal, MD, FCCP
Author and Funding Information

Drs Almendros and Khalyfa contributed equally to this manuscript.

FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

aSection of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL

bCenter for Research Informatics, Biological Sciences Division, The University of Chicago, Chicago, IL

cUnitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona-IDIBAPS, Barcelona, Spain

dCIBER de Enfermedades Respiratorias, Madrid, Spain

CORRESPONDENCE TO: David Gozal, MD, FCCP, Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, KCBD, Rm 4100, 900 E 57th St, Mailbox 4, Chicago, IL, 60637, USA


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(5):1030-1041. doi:10.1016/j.chest.2016.08.1438
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Background  OSA is associated with increased cancer incidence and mortality. Exosomes are vesicles secreted by most cells. They are released into the bloodstream and play a role in tumor progression and metastasis. We evaluated whether the chronic intermittent hypoxia (IH) that characterizes OSA leads to release of tumor-promoting exosomes in the circulation.

Methods  C57/B6 male mice were randomized to 6 weeks of IH or room air (RA). A subgroup was injected with TC1 lung carcinoma cells in the left flank after 2 weeks of IH. Exosomes from mouse plasma and from 10 adult human patients with OSA before and after treatment for 6 weeks were cocultured with mouse TC1 and human adenocarcinoma cells lines. Malignant tumor properties such as proliferation, migration, invasion, and endothelial monolayer disruption were assessed, as was micro-RNA (miRNA), exosomal content, and transcriptomic effects of exosomes on TC1 cells in vitro to identify target genes.

Results  Application of IH-induced exosomes from either IH-exposed tumor-bearing (IH+) or non-tumor-bearing (IH–) mice significantly promoted TC1 malignant properties. Similarly, before adherent treatment, exosomes from patients with OSA significantly enhanced proliferation and migration of human adenocarcinoma cells compared with after adherent treatment. Eleven distinct miRNAs emerged in IH–exposed mice, and their gene targets in TC1 cells were identified.

Conclusions  Circulating exosomes released under IH conditions in vivo selectively enhance specific properties of lung tumor cell cultures. Thus, plasma exosomes participate in the increased tumor aggressiveness observed in patients with OSA.

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