Extracellular vesicles from the infarcted and failing heart drive tumor growth
Authors: Caller T , Shaihov Teper O , Schary Y , Lendengolts D , Rotem I , Peled R , Amit U , Shai R , Glick Saar E , Dominissini D , Boomgarden A , D'Souza-Schorey C , Naftali-Shani N , Leor J 
Published: October 2022

Aims

Heart disease might be an independent risk factor for cancer (reverse cardio-oncology). The co-occurrence of these diseases worsens patients' prognoses and limits therapeutic options. However, the cellular and molecular mechanisms that link heart disease to cancer remain elusive. Therefore, we hypothesized that cardiac extracellular vesicles (cEVs) secreted by diseased hearts carry and disseminate factors that promote tumor growth.

Methods and results

We subjected female mice to myocardial infarction (MI) or sham-MI and 28 days of follow-up. Left ventricular remodeling and dysfunction were assessed by echocardiography. To determine the role of cEVs in tumor growth, we focused on cardiac mesenchymal stromal cells (cMSCs), which play a central role in cardiac repair, remodeling, and fibrosis. We isolated cMSCs from mice hearts 10 or 28 days after MI or sham MI and purified cMSC-EVs from the conditioned medium using size exclusion chromatography. cEVs were characterized by nanoparticle tracking analysis (NTA), the classical EV markers: CD81 and Tumor susceptibility gene 101, and electron microscopy. cMSCs after MI secreted more small EVs than cMSCs from sham-MI (Fig. 1A, p&lt;0.0001). Proteomic and biological process analysis revealed a distinctive profile of cEVs after MI with more EV-encapsulated proteins related to inflammation, angiogenesis, and cell cycle (Fig. 1B). Purified cMSC-EVs were labeled with PKH26 dye and found to target both breast and lung cancer cells in vitro. Colorimetric proliferation assay showed that MI-cEVs facilitated cancer cells proliferation compared with sham-MI cEVs (n=7 in each group, p&lt;0.0001). Furthermore, by scratch assay, MI-cEVs facilitated cancer cell migration two times faster than sham-MI cEVs (Fig. 1C, p=0.0002). Finally, we established 2 models of heart disease with cancer. Lung or breast cancer cells (750x103 or 250x103) were inoculated into the hind limb or mammary pad 10 days before or after MI. Serial ultrasound examinations monitored tumor growth. While MI significantly stimulated lung cancer growth, EV inhibition by GW4869 markedly attenuated the tumorigenic effect of MI and left ventricular (LV) dysfunction (Fig. 1D, p for GW4869 &lt;0.0001). Moreover, we found an inverse correlation between LV ejection fraction (LVEF) and the volume of breast cancer tumors. cEV inhibition by GW4869 attenuated this inverse correlation (for vehicle group: n=14, r=−0.54 and p=0.04. for GW4869 group: n=13, r=−0.43, and p=0.14).

Conclusions

Our results suggest, for the first time, that cMSCs from the infarcted and failing heart secret EVs that target tumor cells and accelerate tumor growth. We propose cEVs as potential mediators and therapeutic targets in patients with concomitant heart disease and cancer.

Funding Acknowledgement

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Seymour Fefer Grant