Human liver stem cell-derived extracellular vesicles enhance cancer stem cell sensitivity to tyrosine kinase inhibitors through Akt/mTOR/PTEN combined modulation

// Valentina Fonsato 1, 2 , Michela De Lena 1, 2 , Stefania Tritta 1, 2 , Alessia Brossa 1, 2 , Ruggero Calvetti 3 , Ciro Tetta 4 , Giovanni Camussi 5 and Benedetta Bussolati 3 1 2i3T, Societa per la gestione dell'incubatore di imprese e per il trasferimento tecnologico, Scarl University of Torino, Torino, Italy 2 Molecular Biotechnology Center, University of Torino, Torino, Italy 3 Department of Molecular Biotechnology and Health Sciences, Torino, Italy 4 Unicyte AG, Oberdorf, NW, Switzerland 5 Department of Medical Sciences, University of Torino, Torino, Italy Correspondence to: Benedetta Bussolati, email: benedetta.bussolati@unito.it Keywords: tumor stem cells; renal cell carcinoma; exosomes; Sunitinib; liver stem cell Received: June 26, 2018      Accepted: October 24, 2018      Published: November 16, 2018 ABSTRACT 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.