Microvesicles released from human renal cancer stem cellsstimulate angiogenesis and formation of lung pre-metastatic niche.

Recent studies suggest that tumor-derived microvesicles (MVs) act as a vehicle for exchange of genetic information among tumor and stromal cells, engendering a favorable microenvironment for cancer development. Within the tumor mass, all cell types may contribute to MV shedding, but specific contributions to tumor progression have yet to be established. Here we report that a subset of tumor initiating cells expressing the mesenchymal stem cell marker CD105 in human renal cell carcinoma release MVs that trigger angiogenesis and promote the formation of a pre-metastatic niche. MVs derived only from CD105-positive cancer stem cells conferred an activated angiogenic phenotype to normal human endothelial cells, stimulating their growth and vessel formation after in vivo implantation in immunocompromised SCID mice. Further, treating SCID mice with MVs shed from CD105-positive cells greatly enhanced lung metastases induced by i.v. injection of renal carcinoma cells. Molecular characterization of CD105-positive MVs defines a set of pro-angiogenic mRNAs and microRNAs implicated in tumor progression and metastases. Our results define a specific source of cancer stem cell-derived MVs that contribute to triggering the angiogenic switch and coordinating metastatic diffusion during tumor progression.