Extracellular vesicles derived from renal cancer stem cells induce a pro-tumorigenic phenotype in mesenchymal stromal cells.

// Rafael Soares Lindoso 1,2,* , Federica Collino 1,3,* and Giovanni Camussi 1 1 Department of Medical Sciences and Molecular Biotechnology Center University of Torino, Torino, Italy 2 Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil 3 Translational Center of Regenerative Medicine Unito/Fresenius Medical Care, Torino, Italy * These authors contributed equally to this work Correspondence to: Giovanni Camussi, email: // Keywords : extracellular vesicles, cancer stem cells, mesenchymal stromal cells, tumor growth, renal carcinoma Received : October 27, 2014 Accepted : February 04, 2015 Published : March 10, 2015 Abstract Renal carcinomas have been shown to contain a population of cancer stem cells (CSCs) that present self-renewing capacity and support tumor growth and metastasis. CSCs were shown to secrete large amount of extracellular vesicles (EVs) that can transfer several molecules (proteins, lipids and nucleic acids) and induce epigenetic changes in target cells. Mesenchymal Stromal Cells (MSCs) are susceptible to tumor signalling and can be recruited to tumor regions. The precise role of MSCs in tumor development is still under debate since both pro- and anti-tumorigenic effects have been reported. In this study we analysed the participation of renal CSC-derived EVs in the interaction between tumor and MSCs. We found that CSC-derived EVs promoted persistent phenotypical changes in MSCs characterized by an increased expression of genes associated with cell migration ( CXCR4 , CXCR7 ), matrix remodeling ( COL4A3 ), angiogenesis and tumor growth (IL-8, Osteopontin and Myeloperoxidase). EV-stimulated MSCs exhibited in vitro an enhancement of migration toward the tumor conditioned medium. Moreover, EV-stimulated MSCs enhanced migration of renal tumor cells and induced vessel-like formation. In vivo, EV-stimulated MSCs supported tumor development and vascularization, when co-injected with renal tumor cells. In conclusion, CSC-derived EVs induced phenotypical changes in MSCs that are associated with tumor growth.