title: Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche.
abstract: Recent studies suggest that tumor-derived microvesicles (MV) act as a vehicle for exchange of genetic information between 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 releases MVs that trigger angiogenesis and promote the formation of a premetastatic 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 severe combined immunodeficient (SCID) mice. Furthermore, 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 proangiogenic 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.
authors.affiliation: Department of Internal Medicine, Molecular Biotechnology Center, University of Torino, Turin, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Grange
authors.forename: Marta
authors.initials: M
authors.lastname: Tapparo
authors.forename: Federica
authors.initials: F
authors.lastname: Collino
authors.forename: Loriana
authors.initials: L
authors.lastname: Vitillo
authors.forename: Christian
authors.initials: C
authors.lastname: Damasco
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Deregibus
authors.forename: Ciro
authors.initials: C
authors.lastname: Tetta
authors.forename: Benedetta
authors.initials: B
authors.lastname: Bussolati
authors.forename: Giovanni
authors.initials: G
authors.lastname: Camussi
mesh_terms: D042501:Angiogenic Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000951:Antigens, Neoplasm / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000473:pathology* / Q000556:secondary; D002478:Cells, Cultured; D000071063:Endoglin; D042783:Endothelial Cells / Q000166:cytology; D058750:Epithelial-Mesenchymal Transition; D055354:Exosomes / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D018189:Immunomagnetic Separation; D007680:Kidney Neoplasms / Q000473:pathology*; D008175:Lung Neoplasms / Q000098:blood supply / Q000556:secondary*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000096:biosynthesis; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000637:transplantation; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000032:analysis; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment
chemical_list: D042501:Angiogenic Proteins; D015703:Antigens, CD; D000951:Antigens, Neoplasm; C064206:ENG protein, human; D000071063:Endoglin; D035683:MicroRNAs; D012334:RNA, Neoplasm; D011956:Receptors, Cell Surface; D020780:Matrix Metalloproteinase 9