title: Reprogramming Malignant Cancer Cells toward a Benign Phenotype following Exposure to Human Embryonic Stem Cell Microenvironment.
abstract: 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.
authors.affiliation: Cancer Research Program, McGill University Health Centre-Research Institute, Montreal, Canada.|Department of Experimental Surgery, Montreal General Hospital, McGill University, Montreal, Canada.
authors.forename: Shufeng
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Cancer Research Program, McGill University Health Centre-Research Institute, Montreal, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdouh
authors.affiliation: Deparment of Obstetrics and Gynecology, Santo Bambino Hospital, Catania, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Arena
authors.affiliation: Department of Surgical Sciences, Organ Transplantation and Advances Technologies, University of Catania, Catania, Italy.
authors.forename: Manuel
authors.initials: M
authors.lastname: Arena
authors.affiliation: Cancer Research Program, McGill University Health Centre-Research Institute, Montreal, Canada.|Department of Surgery, St. Mary Hospital, McGill University, Montreal, Canada.
authors.forename: Goffredo Orazio
authors.initials: GO
authors.lastname: Arena
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002450:Cell Communication; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D017077:Culture Media, Conditioned / Q000494:pharmacology; D055354:Exosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D060787:Neoplasm Grading; D010641:Phenotype; D015398:Signal Transduction; D055153:Stem Cell Niche
chemical_list: D017077:Culture Media, Conditioned