title: Chronic myeloid leukemia-derived exosomes promote tumor growth through an autocrine mechanism.
abstract: BACKGROUND
  Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder in which leukemic cells display a reciprocal t(9:22) chromosomal translocation that results in the formation of the chimeric BCR-ABL oncoprotein, with a constitutive tyrosine kinase activity. Consequently, BCR-ABL causes increased proliferation, inhibition of apoptosis, and altered adhesion of leukemic blasts to the bone marrow (BM) microenvironment. It has been well documented that cancer cells can generate their own signals in order to sustain their growth and survival, and recent studies have revealed the role of cancer-derived exosomes in activating signal transduction pathways involved in cancer cell proliferation. Exosomes are small vesicles of 40-100 nm in diameter that are initially formed within the endosomal compartment, and are secreted when a multivesicular body (MVB) fuses with the plasma membrane. These vesicles are released by many cell types including cancer cells, and are considered messengers in intercellular communication. We have previously shown that CML cells released exosomes able to affect the tumor microenvironment.
  
  
  RESULTS
  CML cells, exposed up to one week, to exosomes showed a dose-dependent increased proliferation compared with controls. Moreover, exosome treatment promotes the formation of LAMA84 colonies in methylcellulose. In a CML xenograft model, treatment of mice with exosomes caused a greater increase in tumor size compared with controls (PBS-treated mice). Real time PCR and Western Blot analysis showed, in both in vitro and in vivo samples, an increase in mRNA and protein levels of anti-apoptotic molecules, such as BCL-w, BCL-xl, and survivin, and a reduction of the pro-apoptotic molecules BAD, BAX and PUMA. We also found that TGF- β1 was enriched in CML-exosomes. Our investigations showed that exosome-stimulated proliferation of leukemia cells, as well as the exosome-mediated activation of an anti-apoptotic phenotype, can be inhibited by blocking TGF-β1 signaling.
  
  
  CONCLUSIONS
  CML-derived exosomes promote, through an autocrine mechanism, the proliferation and survival of tumor cells, both in vitro and in vivo, by activating anti-apoptotic pathways. We propose that this mechanism is activated by a ligand-receptor interaction between TGF-β1, found in CML-derived exosomes, and the TGF- β1 receptor in CML cells.
authors: Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università degli studi di Palermo, sezione di Biologia e Genetica, Via Divisi 83, 90100, Palermo, Italy. stefania.raimondo@unipa.it.
authors: Stefania
authors: S
authors: Raimondo
authors: Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università degli studi di Palermo, sezione di Biologia e Genetica, Via Divisi 83, 90100, Palermo, Italy. laurasaieva@gmail.com.
authors: Laura
authors: L
authors: Saieva
authors: Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università degli studi di Palermo, sezione di Biologia e Genetica, Via Divisi 83, 90100, Palermo, Italy. chiara.corrado@unipa.it.
authors: Chiara
authors: C
authors: Corrado
authors: Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università degli studi di Palermo, sezione di Biologia e Genetica, Via Divisi 83, 90100, Palermo, Italy. simona.fontana@unipa.it.
authors: Simona
authors: S
authors: Fontana
authors: Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università degli studi di Palermo, sezione di Biologia e Genetica, Via Divisi 83, 90100, Palermo, Italy. anna.flugy@unipa.it.
authors: Anna
authors: A
authors: Flugy
authors: Azienda Ospedaliera Ospedali Riuniti Villa Sofia- Cervello, Anatomia Patologica, Palermo, Italy. aroldorizzo@yahoo.it.
authors: Aroldo
authors: A
authors: Rizzo
authors: Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università degli studi di Palermo, sezione di Biologia e Genetica, Via Divisi 83, 90100, Palermo, Italy. giacomo.deleo@unipa.it.
authors: Giacomo
authors: G
authors: De Leo
authors: Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università degli studi di Palermo, sezione di Biologia e Genetica, Via Divisi 83, 90100, Palermo, Italy. riccardo.alessandro@unipa.it.
authors: Riccardo
authors: R
authors: Alessandro
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055354:Exosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000077022:Survivin; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1
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