BACKGROUND:Myocardial infarction (MI) and heart failure are associated with an increased incidence of cancer. However, the mechanism is complex and unclear. Here, we aimed to test our hypothesis that cardiac small extracellular vesicles (sEVs), particularly cardiac mesenchymal stromal cell–derived sEVs (cMSC-sEVs), contribute to the link between post-MI left ventricular dysfunction (LVD) and cancer.METHODS:We purified and characterized sEVs from post-MI hearts and cultured cMSCs. Then, we analyzed cMSC-EV cargo and proneoplastic effects on several lines of cancer cells, macrophages, and endothelial cells. Next, we modeled heterotopic and orthotopic lung and breast cancer tumors in mice with post-MI LVD. We transferred cMSC-sEVs 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.RESULTS:Post-MI hearts, particularly cMSCs, produced more sEVs with proneoplastic cargo than nonfailing hearts did. Proteomic analysis revealed unique protein profiles and higher quantities of tumor-promoting cytokines, proteins, and microRNAs in cMSC-sEVs from post-MI hearts. The proneoplastic effects of cMSC-sEVs varied with different types of cancer, with lung and colon cancers being more affected than melanoma and breast cancer cell lines. Post-MI cMSC-sEVs also activated resting macrophages into proangiogenic and protumorigenic states in vitro. At 28-day follow-up, mice with post-MI LVD developed larger heterotopic and orthotopic lung tumors than did sham-MI mice. Adoptive transfer of cMSC-sEVs from post-MI hearts accelerated the growth of heterotopic and orthotopic lung tumors, and biodistribution analysis revealed accumulating cMSC-sEVs in tumor cells along with accelerated tumor cell proliferation. sEV depletion reduced the tumor-promoting effects of MI, and adoptive transfer of cMSC-sEVs from post-MI hearts partially restored these effects. Finally, spironolactone treatment reduced the number of cMSC-sEVs and suppressed tumor growth during post-MI LVD.CONCLUSIONS:Cardiac sEVs, specifically cMSC-sEVs from post-MI hearts, carry multiple protumorigenic factors. Uptake of cMSC-sEVs by cancer cells accelerates tumor growth. Treatment with spironolactone significantly reduces accelerated tumor growth after MI. Our results provide new insight into the mechanism connecting post-MI LVD to cancer and propose a translational option to mitigate this deadly association.

中文翻译：

---

来自梗塞和衰竭心脏的小细胞外囊泡加速肿瘤生长

背景：心肌梗塞（MI）和心力衰竭与癌症发病率增加有关。然而，其机制复杂且不清楚。在这里，我们的目的是检验我们的假设，即心脏小细胞外囊泡 (sEV)，特别是心脏间充质基质细胞衍生的 sEV (cMSC-sEV)，有助于 MI 后左心室功能障碍 (LVD) 与癌症之间的联系。方法：我们从 MI 后心脏中纯化并表征了 sEV，并培养了 cMSC。然后，我们分析了 cMSC-EV 货物和对几种癌细胞系、巨噬细胞和内皮细胞的促肿瘤作用。接下来，我们对 MI 后 LVD 小鼠的异位和原位肺癌和乳腺癌肿瘤进行建模。我们转移 cMSC-sEV 以评估 sEV 的生物分布及其对肿瘤生长的影响。最后，我们测试了 sEV 消耗和螺内酯治疗对 cMSC-EV 释放和肿瘤生长的影响。 结果：MI 后心脏，特别是 cMSC，比非衰竭心脏产生更多带有促肿瘤物质的 sEV。蛋白质组学分析揭示了 MI 后心脏的 cMSC-sEV 中独特的蛋白质谱和更高数量的促肿瘤细胞因子、蛋白质和 microRNA。cMSC-sEV 的促肿瘤作用因不同类型的癌症而异，其中肺癌和结肠癌比黑色素瘤和乳腺癌细胞系受影响更大。MI 后 cMSC-sEV 还在体外激活静息巨噬细胞进入促血管生成和促肿瘤生成状态。在 28 天的随访中，MI 后 LVD 小鼠比假 MI 小鼠出现了更大的异位和原位肺肿瘤。来自 MI 后心脏的 cMSC-sEV 的过继转移加速了异位和原位肺肿瘤的生长，生物分布分析显示，cMSC-sEV 在肿瘤细胞中积累，并加速了肿瘤细胞的增殖。sEV 耗竭降低了 MI 的肿瘤促进作用，而从 MI 后心脏过继转移 cMSC-sEV 部分恢复了这些作用。最后，螺内酯治疗减少了 cMSC-sEV 的数量，并抑制了 MI 后 LVD 期间的肿瘤生长。结论：心脏 sEV，特别是来自 MI 后心脏的 cMSC-sEV，携带多种促肿瘤因子。癌细胞摄取 cMSC-sEV 可加速肿瘤生长。螺内酯治疗可显着减少心肌梗死后肿瘤的加速生长。我们的研究结果为 MI 后 LVD 与癌症之间的联系机制提供了新的见解，并提出了一种缓解这种致命关联的转化方案。