Harnessing the heart’s resistance to malignant tumors: cardiac-derived extracellular vesicles decrease fibrosarcoma growth and leukemia-related mortality in rodents

// Lilian Grigorian-Shamagian 1, * , Soraya Fereydooni 1, 2, * , Weixin Liu 1 , Antonio Echavez 1 and Eduardo Marbán 1 1 Cedars-Sinai Heart Institute, Los Angeles, CA, United States of America 2 Department of Biology, Stanford University, Stanford, CA, United States of America * Co-first authors Correspondence to: Eduardo Marbán, email: Eduardo.Marban@csmc.edu Keywords: extracellular vesicles; cancer; fibrosarcoma; cardiosphere-derived cells; oncogenic safety Received: June 22, 2017     Accepted: July 14, 2017     Published: August 24, 2017 ABSTRACT The heart is known for its resistance to cancer. Although different conjectures have been proposed to explain this phenomenon, none has been tested. We propose that the heart microenvironment may exert anti-cancer properties. So, our objective was to test the anti-oncogenic potential of cardiac-derived extracellular vesicles (EVs). For that EVs secreted by cardiosphere-derived cells (CDCs, heart progenitor cells) were tested in vitro on fibrosarcoma HT1080. In vivo models comprised the xenograft HT1080 fibrosarcoma in athymic mice (n=35), and spontaneous acute lymphocyte leukemia in old rats (n=44). CDC-EVs were compared with two control groups: EVs secreted by bone-marrow derived mesenchymal stem cells (MSC-EVs) and phosphate-buffered saline (PBS). Injection of CDC-EVs led to a 2.5-fold decrease of fibrosarcoma growth in mice (p<0.01 and p<0.05 for human and rat EVs, respectively) vs PBS group. The effect was associated with 2-fold decrease of tumor cells proliferation (p<0.001) and 1.5-fold increase of apoptosis (p<0.05) in CDC-EV vs PBS mice. Salutary changes in tumor gene and protein expression were observed in CDC-EV animals. CDC-EVs reduced tumor vascularization compared with PBS (p<0.05) and MSC-EVs (p<0.01). Moreover, CDC-EVs increased leukemia-free survival (p<0.05) in old rats vs PBS. MiR-146, highly enriched in CDC-EVs, may be implicated in part of the observed effects. In conclusion, this study presents the first evidence that ties together the long-recognized enigma of the “heart immunity to cancer” with an antioncogenic effect of heart-derived EVs. These findings open up cancer as a new therapeutic target for CDC-EVs.