Human liver stem cell-derived microvesicles inhibit hepatoma growth in SCID mice by delivering antitumor microRNAs.
Microvesicles (MVs) play a pivotal role in cell-to-cell communication. Recent studies demonstrated that MVs may transfer genetic information between cells. Here, we show that MVs derived from human adult liver stem cells (HLSC) may reprogram in vitro HepG2 hepatoma and primary hepatocellular carcinoma cells by inhibiting their growth and survival. In vivo intratumor administration of MVs induced regression of ectopic tumors developed in SCID mice. We suggest that the mechanism of action is related to the delivery of microRNAs (miRNAs) from HLSC-derived MVs (MV-HLSC) to tumor cells on the basis of the following evidence: (a) the rapid, CD29-mediated internalization of MV-HLSC in HepG2 and the inhibition of tumor cell growth after MV uptake; (b) the transfer by MV-HLSC of miRNAs with potential antitumor activity that was downregulated in HepG2 cells with respect to normal hepatocytes; (c) the abrogation of the MV-HLSC antitumor effect after MV pretreatment with RNase or generation of MVs depleted of miRNAs; (d) the relevance of selected miRNAs was proven by transfecting HepG2 with miRNA mimics. The antitumor effect of MV-HLSC was also observed in tumors other than liver such as lymphoblastoma and glioblastoma. These results suggest that the delivery of selected miRNAs by MVs derived from stem cells may inhibit tumor growth and stimulate apoptosis.
Department of Internal Medicine, Research Center for Experimental Medicine (CeRMS) and Center of Molecular Biotechnology, University of Torino, Torino, Italy.
Valentina
V
Fonsato
Federica
F
Collino
Maria Beatriz
MB
Herrera
Claudia
C
Cavallari
Maria Chiara
MC
Deregibus
Barbara
B
Cisterna
Stefania
S
Bruno
Renato
R
Romagnoli
Mauro
M
Salizzoni
Ciro
C
Tetta
Giovanni
G
Camussi
D053687:Adult Stem Cells / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D048708:Cell Growth Processes / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D008099:Liver / Q000166:cytology / Q000502:physiology*; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics; D055806:Microvessels / Q000502:physiology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D035683:MicroRNAs