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

Valentina Fonsato,Stefania Tritta,Alessia Brossa,Giovanni Camussi,Ciro Tetta,Michela De Lena,Benedetta Bussolati,Ruggero Calvetti

doi:10.18632/oncotarget.26319

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.

Highlights

Renal cell carcinoma (RCC) is a common solid tumour associated to high mortality with frequent metastatic spread and high recurrence within 5 years [1]
We evaluated whether extracellular vesicles (EV) derived from human liver stem cells (HLSC) could act in synergy with tyrosine kinase inhibitors (TKIs) on apoptosis of Cancer Stem Cells (CSC) isolated from renal carcinomas
We found that HLSC-EVs in combination with Sunitinb or Sorafenib significantly increased renal CSCs apoptosis induced by low TKI dose

Summary

Introduction

Renal cell carcinoma (RCC) is a common solid tumour associated to high mortality with frequent metastatic spread and high recurrence within 5 years [1]. A group of tyrosine kinase inhibitors (TKIs) was introduced in the clinical practice as first line treatment for metastatic RCC. Their anticancer activity is related to the inhibition of growth factor receptors overexpressed in renal cancer and responsible, at least in part, for tumor angiogenesis and cell proliferation [4]. A major limit of TKI long-term anti-tumor effect is the development of resistance in the vast majority of cases [7]

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