Zhou Shufeng, Abdouh Mohamed, Arena Vincenzo, Arena Manuel, Arena Goffredo Orazio
Cancer Research Program, McGill University Health Centre-Research Institute, Montreal, Canada.
Department of Experimental Surgery, Montreal General Hospital, McGill University, Montreal, Canada.
PLoS One. 2017 Jan 9;12(1):e0169899. doi: 10.1371/journal.pone.0169899. eCollection 2017.
The embryonic microenvironment is well known to be non-permissive for tumor development because early developmental signals naturally suppress the expression of proto-oncogenes. In an analogous manner, mimicking an early embryonic environment during embryonic stem cell culture has been shown to suppress oncogenic phenotypes of cancer cells. Exosomes derived from human embryonic stem cells harbor substances that mirror the content of the cells of origin and have been reported to reprogram hematopoietic stem/progenitor cells via horizontal transfer of mRNA and proteins. However, the possibility that these embryonic stem cells-derived exosomes might be the main effectors of the anti-tumor effect mediated by the embryonic stem cells has not been explored yet. The present study aims to investigate whether exosomes derived from human embryonic stem cells can reprogram malignant cancer cells to a benign stage and reduce their tumorigenicity. We show that the embryonic stem cell-conditioned medium contains factors that inhibit cancer cell growth and tumorigenicity in vitro and in vivo. Moreover, we demonstrate that exosomes derived from human embryonic stem cells display anti-proliferation and pro-apoptotic effects, and decrease tumor size in a xenograft model. These exosomes are also able to transfer their cargo into target cancer cells, inducing a dose-dependent increase in SOX2, OCT4 and Nanog proteins, leading to a dose-dependent decrease of cancer cell growth and tumorigenicity. This study shows for the first time that human embryonic stem cell-derived exosomes play an important role in the tumor suppressive activity displayed by human embryonic stem cells.
众所周知，胚胎微环境不利于肿瘤发展，因为早期发育信号会自然抑制原癌基因的表达。以类似的方式，在胚胎干细胞培养过程中模拟早期胚胎环境已被证明可抑制癌细胞的致癌表型。源自人类胚胎干细胞的外泌体含有反映其来源细胞内容物的物质，并且据报道可通过mRNA和蛋白质的水平转移对造血干/祖细胞进行重编程。然而，这些源自胚胎干细胞的外泌体可能是胚胎干细胞介导的抗肿瘤作用的主要效应物这一可能性尚未得到探索。本研究旨在调查源自人类胚胎干细胞的外泌体是否能够将恶性癌细胞重编程至良性阶段并降低其致瘤性。我们发现，胚胎干细胞条件培养基含有在体外和体内抑制癌细胞生长和致瘤性的因子。此外，我们证明源自人类胚胎干细胞的外泌体具有抗增殖和促凋亡作用，并在异种移植模型中减小肿瘤大小。这些外泌体还能够将其内含物转移至靶癌细胞，导致SOX2、OCT4和Nanog蛋白呈剂量依赖性增加，进而使癌细胞生长和致瘤性呈剂量依赖性降低。本研究首次表明，源自人类胚胎干细胞的外泌体在人类胚胎干细胞所表现出的肿瘤抑制活性中发挥重要作用。
