Circulating exosomes potentiate tumor malignant properties in a mouse model of chronic sleep fragmentation

Abstract

BackgroundChronic sleep fragmentation (SF) increases cancer aggressiveness in mice. Exosomes exhibit pleiotropic biological functions, including immune regulatory functions, antigen presentation, intracellular communication and inter-cellular transfer of RNA and proteins. We hypothesized that SF-induced alterations in biosynthesis and cargo of plasma exosomes may affect tumor cell properties.ResultsSF-derived exosomes increased tumor cell proliferation (~13%), migration (~2.3-fold) and extravasation (~10%) when compared to exosomes from SC-exposed mice. Similarly, Pre exosomes from OSA patients significantly enhanced proliferation and migration of human adenocarcinoma cells compared to Post. SF-exosomal cargo revealed 3 discrete differentially expressed miRNAs, and exploration of potential mRNA targets in TC1 tumor cells uncovered 132 differentially expressed genes that encode for multiple cancer-related pathways.MethodsPlasma-derived exosomes from C57/B6 mice exposed to 6 wks of SF or sleep control (SC), and from adult human patients with obstructive sleep apnea (OSA) before (Pre) and after adherent treatment for 6 wks (Post) were co-cultured with mouse lung TC1 or human adenocarcinoma tumor cell lines, respectively. Proliferation, migration, invasion, endothelial barrier integrity and extravasation assays of tumor cells were performed. Plasma mouse exosomal miRNAs were profiled with arrays, and transcriptomic assessments of TC1 cells exposed to SF or SC exosomes were conducted to identify gene targets.ConclusionsChronic SF induces alterations in exosomal miRNA cargo that alter the biological properties of TC1 lung tumor cells to enhance their proliferative, migratory and extravasation properties, and similar findings occur in OSA patients, in whom SF is a constitutive component of their sleep disorder. Thus, exosomes could participate, at least in part, in the adverse cancer outcomes observed in OSA.

Role of Exosomes in Cancer-Related Cognitive Impairment

“…Nevertheless, Khalyfa et al showed that chronic sleep fragmentation can alter exosomal miRNA cargo and affect the biological function (i.e., proliferative, migratory, and extravasation properties) of lung tumor cells in mice [87]. Similar results were also observed when human adenocarcinoma tumor cell lines were treated with plasma exosomes derived from patients with obstructive sleep apnea [87]. It was also reported that physical fatigue can be linked to the exosomal transfer of miRNAs affecting skeletal muscle function [88].…”

“…While the use of proteomics to understand cancer-related fatigue remains to be established [85], Minton et al demonstrated differences in plasma protein expression in cancer-related fatigue syndrome compared to non-fatigued control subjects [86]. Nevertheless, Khalyfa et al showed that chronic sleep fragmentation can alter exosomal miRNA cargo and affect the biological function (i.e., proliferative, migratory, and extravasation properties) of lung tumor cells in mice [87]. Similar results were also observed when human adenocarcinoma tumor cell lines were treated with plasma exosomes derived from patients with obstructive sleep apnea [87].…”

Exosomal long noncoding RNA CRNDE-h as a novel serum-based biomarker for diagnosis and prognosis of colorectal cancer

“…Circulating exosomes carry regulatory RNA molecules and play a role in long distance cell-cell communication[15]. Emerging evidences have shown that the expression of specific exosomal lncRNAs are correlated with the clinicopathological characteristics of cancer and thus may function as meaningful biomarkers [16–18].…”

Elevation of circulating microRNA levels in obese children compared to healthy controls

“…MicroRNAs are small non‐coding RNAs (~22 nucleotides) that function in the post‐transcriptional regulation of gene expression. Several recent studies have evaluated their potential as biomarkers in a variety of paediatric conditions, including diabetes, endothelial dysfunction in obesity, leukaemia, asthma, autism and cholestatic liver disease . In addition to the possibility of improved sensitivity and specificity, miRNAs may appear in the serum earlier in disease progression than many commonly assayed protein biomarkers.…”