Human liver stem cell-derived extracellular vesicles enhance cancer stem cell sensitivity to tyrosine kinase inhibitors through Akt/mTOR/PTEN combined modulation
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Valentina Fonsato1,2, Michela De Lena1,2, Stefania Tritta1,2, Alessia Brossa1,2, Ruggero Calvetti3, Ciro Tetta4, Giovanni Camussi5 and Benedetta Bussolati3
12i3T, Società per la gestione dell'incubatore di imprese e per il trasferimento tecnologico, Scarl University of Torino, Torino, Italy
2Molecular Biotechnology Center, University of Torino, Torino, Italy
3Department of Molecular Biotechnology and Health Sciences, Torino, Italy
4Unicyte AG, Oberdorf, NW, Switzerland
5Department of Medical Sciences, University of Torino, Torino, Italy
Benedetta Bussolati, email: [email protected]
Keywords: tumor stem cells; renal cell carcinoma; exosomes; Sunitinib; liver stem cell
Received: June 26, 2018 Accepted: October 24, 2018 Published: November 16, 2018
It is well recognized that Cancer Stem Cells (CSCs) sustain the initiation, the maintenance and the recurrence of tumors. We previously reported that extracellular vesicles (EVs) derived from human liver stem cells (HLSCs) were able to limit tumor development. In this study, we evaluated whether EV derived from HLSCs could act in synergy with tyrosine kinase inhibitors (TKIs) on apoptosis of CSCs isolated from renal carcinomas. For this purpose, we administered to renal CSCs, HLSC-EVs and TKIs, as co-incubation or sequential administration. We found that HLSC-EVs in combination with Sunitinb or Sorafenib significantly increased renal CSCs apoptosis induced by low TKI dose. At variance, no synergistic effect was observed when bone marrow mesenchymal stem cell-derived EVs were used. In particular, renal CSCs chemosensitivity to TKIs was enhanced when HLSC-EVs were either co-administered with TKIs or added after, but not before. CSC apoptosis was also incremented at a percentage comparable to that of co-administration when TKIs were loaded in HLSC-EVs. By a mechanistic point of view, Akt/mTOR and Erk and Creb intracellular pathways, known to be pivotal in the induction of tumor growth and survival, appeared modulated as consequence of TKIs/HLSC-EVs co-administration. Together, our results indicate that the synergistic effect of HLSC-EVs with TKIs may increase the response to TKIs at low doses, providing a rational for their combined use in the treatment of renal carcinoma.
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