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Original Research |

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, DVM, PhD; Jorge Andrade, PhD; Ramon Farré, PhD; David Gozal, MD, MBA, FCCP
Author and Funding Information

Sources Of Support: DG is supported by the Herbert T. Abelson Chair in Pediatrics. IA was supported by Beatriu de Pinós fellowship from Generalitat de Catalunya / Marie Curie Actions (2010 BP_A2 00023).

Conflict of Interest: The authors have no conflicts of interest to declare.

1Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL, USA

2Center for Research Informatics, Biological Sciences Division, The University of Chicago, Chicago, IL, USA

3Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona-IDIBAPS, Barcelona, Spain

4CIBER de Enfermedades Respiratorias, Madrid, Spain

Corresponding Author: David Gozal, MD, MBA, Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, KCBD, Room 4100, 900 E. 57th Street, Mailbox 4, Chicago, IL, 60637, USA.


Copyright 2016, . All Rights Reserved.


Chest. 2016. doi:10.1016/j.chest.2016.08.1438
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Abstract

Background  Obstructive sleep apnea (OSA) is associated with increased cancer incidence and mortality. Exosomes are vesicles secreted by most cells, are released into the bloodstream, and play a role in tumor progression and metastasis. Here, we evaluated whether the chronic intermittent hypoxia (IH) that characterizes OSA leads to release of tumor-promoting exosomes in circulation.

Methods  C57/B6 male mice were randomized to 6 weeks of IH or room air (RA). A subgroup of the mice 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 (Pre) and after adherent treatment for 6 wks (Post) were co-cultured with mouse TC1 and human adenocarcinoma cells lines. Malignant tumor properties such as proliferation, migration, invasion and endothelial monolayer disruption were assessed, as well as 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-bearing mice IH (-) significantly promoted TC1 malignant properties. Similarly, Pre exosomes from OSA patients significantly enhanced proliferation and migration of human adenocarcinoma cells compared to Post. 11 distinct miRNAs emerged in IH (-) mice and their gene targets in TC1 cells were identified.

Conclusion  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 OSA patients.


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