Circulating extracellular vesicle-enriched fraction in heart failure with reduced ejection fraction and incident cancer
E Bianconi, A De Palma, D Perico, S Bruno, F Fumagalli, E Nicolis, E Rulli, D Ceresa, A Costa, C Vitale, R Latini, P L Mauri, P AmeriAbstract
Aims
Previous studies found increased cancer incidence in patients with heart failure with reduced ejection fraction (HFrEF). We sought to explore the biological correlates of the association of HFrEF with cancer in humans.
Methods
and results: Among participants in the GISSI-HF trial with HFrEF and available baseline plasma samples, we selected those who developed solid cancer (cases) and matched them with controls without cancer by age, sex, NYHA class, and follow-up duration. We isolated the plasma extracellular vesicle (EV)-enriched fraction, in which EVs were confirmed by western blot for CD9, FLOTILLIN-1, ALIX and TSG101, and by nanoparticle tracking analysis (mean particle diameter <200 nm). The protein content of EV preparations was characterized by nanoliquid chromatography-high resolution tandem mass spectrometry. Of 940 identified proteins, 148 were differentially expressed between EV preparations from cases (EVs-cases) and controls (EVs-controls) and were related to biological functions implicated in cancer growth, particularly apoptosis and spliceosome/transcriptome regulation. Next, we explored the effects of EVs-cases and EVs-controls in MCF7 breast cancer cells and run confirmatory experiments with another 2 cell lines, HCT116 (colon) and A549 (lung). Apoptosis, as determined by caspase 3 cleavage, was blunted by EVs-cases in MCF7, but not in HCT116 and A549 cells. Screening qPCR pointed out NR3C1, encoding glucocorticoid receptor, as a spliceosome/transcription modulator affected by EVs-cases. Targeted qPCR confirmed that it was reduced by EVs-cases in A549 cells.
Conclusions
Circulating EV-enriched fractions from patients with HFrEF and incident cancer have a distinct proteomic signature and might modulate human cancer cell biology.