title: Expression Profiling of Circulating Microvesicles Reveals Intercellular Transmission of Oncogenic Pathways.
abstract: Circulating microvesicles have been described as important players in cell-to-cell communication carrying biological information under normal or pathologic condition. Microvesicles released by cancer cells may incorporate diverse biomolecules (e.g., active lipids, proteins, and RNA), which can be delivered and internalized by recipient cells, potentially altering the gene expression of recipient cells and eventually impacting disease progression. Leukemiain vitromodel systems were used to investigate microvesicles as vehicles of protein-coding messages. Several leukemic cells (K562, LAMA-87, TOM-1, REH, and SHI-1), each carrying a specific chromosomal translocation, were analyzed. In the leukemic cells, these chromosomal translocations are transcribed into oncogenic fusion transcripts and the transfer of these transcripts was monitored from leukemic cells to microvesicles for each of the cell lines. Microarray gene expression profiling was performed to compare transcriptomes of K562-derived microvesicles and parental K562 cells. The data show that oncogenicBCR-ABL1transcripts and mRNAs related to basic functions of leukemic cells were included in microvesicles. Further analysis of microvesicles cargo revealed a remarkable enrichment of transcripts related to cell membrane activity, cell surface receptors, and extracellular communication when compared with parental K562 cells. Finally, coculturing of healthy mesenchymal stem cells (MSC) with K562-derived microvesicles displayed the transfer of the oncogenic message, and confirmed the increase of target cell proliferation as a function of microvesicle dosage.Implications:This study provides novel insight into tumor-derived microvesicles as carriers of oncogenic protein-coding messages that can potentially jeopardize cell-directed therapy, and spread to other compartments of the body.Mol Cancer Res; 15(6); 683-95. ©2017 AACR.
authors.affiliation: Department of Women's and Children's Health, University of Padova, Padova, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Milani
authors.affiliation: Department of Women's and Children's Health, University of Padova, Padova, Italy.
authors.forename: Tobia
authors.initials: T
authors.lastname: Lana
authors.affiliation: Department of Women's and Children's Health, University of Padova, Padova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bresolin
authors.affiliation: Istituto di Ricerca Pediatrica Città della Speranza (IRP), Padova, Italy.
authors.forename: Sanja
authors.initials: S
authors.lastname: Aveic
authors.affiliation: Istituto Oncologico Veneto IRCCS, Padova, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Pastò
authors.affiliation: Department of Women's and Children's Health, University of Padova, Padova, Italy.|Istituto di Ricerca Pediatrica Città della Speranza (IRP), Padova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Frasson
authors.affiliation: Department of Women's and Children's Health, University of Padova, Padova, Italy. truustekronnie@unipd.it.
authors.forename: Geertruy
authors.initials: G
authors.lastname: Te Kronnie
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D000067128:Extracellular Vesicles / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000502:physiology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D012333:RNA, Messenger; D015398:Signal Transduction; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D014408:Biomarkers, Tumor; D050676:Core Binding Factor Alpha 2 Subunit; D016044:Fusion Proteins, bcr-abl; D051788:Myeloid-Lymphoid Leukemia Protein; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; C447400:MLL-AF6 fusion protein, human; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein