Extracellular vesicles from hypoxic cardiomyocytes enhance growth and pulmonary colonization of tumor cells associated with fibroblast activation

Cancer is a major cause of mortality in patients with heart failure, and myocardial infarction (MI) has been implicated in promoting tumor progression. Fibroblasts are important stromal components involved in tumor microenvironment formation and pulmonary colonization of tumor cells, but whether myocardial infarction (MI) enhances tumor progression through extracellular vesicles (EVs)-mediated cardiomyocyte–fibroblast communication remains unclear. Tumor growth was assessed in heterotopic mouse models with or without MI. Cardiomyocyte-derived extracellular vesicles (EVs) were characterized by proteomic analysis, and their effects on fibroblast activation, extracellular matrix remodeling, and pulmonary tumor colonization were evaluated using in vitro assays and in vivo mouse models. The functional significance of EVs-associated ANGPTL4 was determined by genetic overexpression and silencing approaches in cardiomyocytes, followed by assessment of fibroblast activation and tumor colonization. A retrospective clinical study compared pulmonary nodule progression and plasma ANGPTL4 levels between MI and non-MI patients. MI promoted tumor growth and fibroblast activation, which were attenuated by EV depletion and partially restored by administration of MI-heart-derived EVs. EVs derived from hypoxic cardiomyocytes enhanced fibroblast activation and were associated with increased pulmonary colonization of tumor cells. Proteomic analysis and functional studies identified EV-associated ANGPTL4 from hypoxic cardiomyocytes as a mediator of fibroblast activation in vitro, and suggested a potential role in pulmonary tumor colonization. Clinically, MI patients exhibited increased pulmonary nodule progression and elevated ANGPTL4 levels in plasma-derived EVs. These findings reveal a previously unrecognized reverse cardio-oncology mechanism in which EVs derived from hypoxic cardiomyocytes were associated with fibroblast activation and tumor growth, and may contribute to pulmonary colonization of tumor cells. This work provides mechanistic insight into how myocardial infarction may enhance tumor progression and increase susceptibility to pulmonary colonization.