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.
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.
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.
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.