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.
Highlights
The heart is known for its immunity to cancer
After HT1080 cells were incubated for 96 hours with rat Cardiospherederived cells (CDCs)-extracellular vesicles (EVs) or serum-free medium (SF) alone in vitro (Supplementary Figure 1A), significant differences were observed in 11 of 84 proteins analyzed (Figure 1A)
Most of the observed differences suggested a negative impact of CDCderived EVs (CDC-EV) on pathways associated with cancer
Summary
The heart is known for its immunity to cancer. In contrast to other organs, the overall incidence of primary heart tumors was only 0.02% in an autopsy series in the United States, and only one-quarter of them were malignant [1]. Terminal differentiation and low turnover of cardiomyocytes were proposed as the main mechanisms of heart resistance to tumor formation [2]. This premise is brought into question by the facts that the heart contains a predominantly non-cardiomyocyte, proliferating population of fibroblasts, endothelial and vascular smooth muscle cells, which constitute ~70% of all cells in the adult heart [3]. The incidence of malignancies in the central nervous system [4], characterized by a low rate of cell division, is much higher www.impactjournals.com/oncotarget than that in heart. The unceasing and efficient oxygenconsuming metabolism of the heart, recently proposed as a potential anti-cancer mechanism [5], is challenged by the low incidence of cancer in many cardiac diseases related to altered oxygen supply-consumption balance (i.e. cyanotic congenital heart disease)
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