Harnessing the heart's resistance to malignant tumors: cardiac-derived extracellular vesicles decrease fibrosarcoma growth and leukemia-related mortality in rodents.
Harnessing the heart's resistance to malignant tumors: cardiac-derived extracellular vesicles decrease fibrosarcoma growth and leukemia-related mortality in rodents.
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DOI：
10.18632/oncotarget.20454
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发表时间：
2017-11-21
期刊：
影响因子：
--
通讯作者：
Marbán E
中科院分区：
文献类型：
--
作者：
Grigorian-Shamagian L;Fereydooni S;Liu W;Echavez A;Marbán E
心脏以其对癌症的抵抗力而闻名。虽然人们提出了不同的理论来解释这一现象，但没有一个经过测试。我们认为心脏微环境可能发挥抗癌作用。因此，我们的目标是测试心脏来源的细胞外囊泡（EV）的抗癌潜力。为此，在纤维肉瘤HT 1080上体外测试了由心球衍生细胞（CDC，心脏祖细胞）分泌的EV。在体内模型包括异种移植HT 1080纤维肉瘤在无胸腺小鼠（n=35），和自发性急性淋巴细胞白血病在老年大鼠（n=44）。将CDC-EV与两个对照组进行比较：由骨髓来源的间充质干细胞（MSC-EV）和磷酸盐缓冲盐水（PBS）分泌的EV。与PBS组相比，注射CDC-EV导致小鼠中纤维肉瘤生长减少2.5倍（对于人和大鼠EV，分别为p<0.01和p<0.05）。该效果与CDC-EV与PBS小鼠中肿瘤细胞增殖的2倍降低（p<0.001）和凋亡的1.5倍增加（p<0.05）相关。在CDC-EV动物中观察到肿瘤基因和蛋白表达的有益变化。与PBS（p<0.05）和MSC-EV（p<0.01）相比，CDC-EV减少了肿瘤血管形成。此外，与PBS相比，CDC-EV增加了老年大鼠的无白血病存活率（p<0.05）。在CDC-EV中高度富集的MiR-146可能与所观察到的效应的一部分有关。总之，这项研究提出了第一个证据，将长期公认的“心脏对癌症的免疫力”之谜与心脏衍生EV的抗癌作用联系在一起。这些发现使癌症成为CDC-EV的新治疗靶点。
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.
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影响因子：
4.5
作者：
Grillari, Johannes;Hackl, Matthias;Grillari-Voglauer, Regina
通讯作者：
Grillari-Voglauer, Regina
影响因子：
39.3
作者：
Aminzadeh, Mohammad A.;Tseliou, Eleni;Marban, Eduardo
通讯作者：
Marban, Eduardo
影响因子：
11.2
作者：
Hurst DR;Edmonds MD;Scott GK;Benz CC;Vaidya KS;Welch DR
通讯作者：
Welch DR
影响因子：
8
作者：
Comito, G.;Giannoni, E.;Chiarugi, P.
通讯作者：
Chiarugi, P.
影响因子：
11.2
作者：
Grange, Cristina;Tapparo, Marta;Camussi, Giovanni
通讯作者：
Camussi, Giovanni