Small Extracellular Vesicles from Failing Heart Accelerate Tumor Growth

BackgroundMyocardial infarction (MI) and heart failure (HF) are associated with an increased incidence of cancer. The mechanism is complex and unclear. Here, we aimed to test our hypothesis that cardiac small extracellular vesicles (sEVs), particularly cardiac mesenchymal stromal cells-derived sEVs (cMSC-sEVs), contribute to the link between post-MI HF and cancer. MethodsWe purified and characterized sEVs from the whole heart and cultured cMSCs. Then, we analyzed cMSC-EV cargo and pro-neoplastic effects on several types of cancer cell lines, macrophages, and endothelial cells. Next, we modeled post-MI HF along with heterotopic and orthotopic lung and breast cancer tumors in mice. We used cMSC-sEV transfer to assess sEV biodistribution and its effect on tumor growth. Finally, we tested the effects of sEV depletion and spironolactone treatment on cMSC-EV release and tumor growth. ResultsPost-MI hearts, particularly cMSCs, produced more sEVs with pro-neoplastic cargo than non-failing hearts did. Proteomic analysis revealed unique protein profiles and higher quantities of tumor-promoting cytokines, proteins, and microRNAs in cMSC-sEVs from failing hearts. The pro-neoplastic effects of cMSC-sEVs varied with different types of cancer cells, substantially affecting lung cancer cells relative to other more aggressive cancer cell lines. We also found that post-MI cMSC-sEVs activated resting macrophages into pro-angiogenic and pro-tumorigenic states in vitro. At 28-day follow-up analysis, mice with post-MI HF developed larger lung tumors than did sham-MI mice. Adoptive transfer of cMSC-sEVs from failing hearts accelerated lung tumor growth, and biodistribution analysis revealed an accumulating cMSC- sEVs in tumor cells along with accelerated tumor cell proliferation. Significantly, sEV depletion reduced the tumor-promoting effects of HF, and adoptive transfer of cMSC-sEVs from failing hearts partially restored it. Finally, post-MI spironolactone treatment reduced the number of cMSC-sEVs and suppressed tumor growth during post-MI HF. ConclusionsFor the first time, we show that cardiac sEVs, specifically cMSC-sEVs from post-MI failing hearts, carry multiple pro-tumorigenic factors. Uptake of cMSC-sEVs by cancer cells accelerates tumor growth. Post-MI spironolactone treatment reduces the associated tumor growth. Thus, we provide new insight into the link between post-MI HF and cancer and propose a translational option to mitigate this deadly association.