Extracellular vesicles in onco-nephrology

Abstract

Extracellular vesicles (EVs) are important mediators of intercellular communication in cancer and in normal tissues. EVs transfer biologically active molecules from the cell of origin to recipient cells. This review summarizes the studies on EVs derived from renal cell carcinoma and from a subpopulation of CD105-positive renal cancer stem cells. While EVs from renal cell carcinoma show mild biological activity, EVs from renal cancer stem cells enhance tumor angiogenesis and metastasis formation. The effect is probably due to the transfer of proangiogenic RNA cargo to endothelial cells, which acquire an activated angiogenic phenotype. In vivo, treatment with EVs favors the formation of a premetastatic niche in the lungs. Moreover, EVs derived from renal cancer stem cells modify gene expression in mesenchymal stromal cells, enhancing the expression of genes involved in matrix remodeling, cell migration, and tumor growth. Mesenchymal stromal cells preconditioned with tumor EVs and then coinjected in vivo with renal cancer cells support tumor growth and vessel formation. Finally, tumor EVs promote tumor immune escape by inhibiting the differentiation process of dendritic cells and the activation of T cells. Thus, tumor-derived EVs act on the microenvironment favoring tumor aggressiveness, may contribute to angiogenesis through both direct and indirect mechanisms and are involved in tumor immune escape.

Fig. 1. Role of rCSC-EVs in RCC. Renal carcinoma contains tumoral cells (TC) that are CD105-negative and cancer stem cells (rCSCs) that are CD105-positive. Renal cancer stem cells that are CD105-positive release EVs (rCSC-EVs) that are able to promote tumor growth.

There are more than 24 upregulated miRNAs, including miR-200c miR-92 and miR-141, in CSC-EVs compared to tumoral cell-derived EVs (TC-EVs). Unlike TC-EVs, CSC-EVs carry several mRNAs of proangiogenic genes, such as VEGF, fibroblast growth factor 2 (FGF2), angiopoietin 1, ephrin A3, MMP2 and MMP9. Additionally, HLA-G protein was enriched in rCSC-EVs compared to that in TC-EVs. Moreover, rCSC-EVs support cancer development by several mechanisms. These vesicles were shown to promote tumor angiogenesis in vitro and in vivo and to promote apoptosis resistance following treatment with anticancer drug doxorubicin. Moreover, rCSC-EVs were proven to favor lung premetastatic niche formation through the upregulation of VEGFR1, VEGF, MMP2 and MMP9 in target tissue. In addition, rCSC-EVs can promote MSC migration inducing the upregulation of genes, such as MMP1, MMP3, CXCR4, MMP2, COL4A3 and CXCR7. MSCs stimulated with rCSC-EVs released IL-8, myeloperoxidase (MPO) and osteopontin (OPN) at higher concentrations, promoted cancer angiogenesis and tumor cell migration and increased tumor development in vivo. Finally, rCSC-EVs were shown to mediate cancer immunosuppression by reducing dendritic cell (DC) differentiation and activation. In particular, rCSC-EVs contained higher levels of HLA-G compared to TC-EVs and decreased the expression of activation markers CD83 and CD40, costimulatory molecules CD80 and CD86, and the antigen-presenting molecule HLA-DR in DCs