Role of Extracellular Vesicles in Hematological Malignancies

In recent years the role of tumor microenvironment in the progression of hematological malignancies has been widely recognized. Recent studies have focused on how cancer cells communicate within the microenvironment. Among several factors (cytokines, growth factors, and ECM molecules), a key role has been attributed to extracellular vesicles (EV), released from different cell types. EV (microvesicles and exosomes) may affect stroma remodeling, host cell functions, and tumor angiogenesis by inducing gene expression modulation in target cells, thus promoting cancer progression and metastasis. Microvesicles and exosomes can be recovered from the blood and other body fluids of cancer patients and contain and deliver genetic and proteomic contents that reflect the cell of origin, thus constituting a source of new predictive biomarkers involved in cancer development and serving as possible targets for therapies. Moreover, due to their specific cell-tropism and bioavailability, EV can be considered natural vehicles suitable for drug delivery. Here we will discuss the recent advances in the field of EV as actors in hematological cancer progression, pointing out the role of these vesicles in the tumor-host interplay and in their use as biomarkers for hematological malignancies.

[1]  O. De Wever,et al.  Bone marrow stromal cell-derived exosomes as communicators in drug resistance in multiple myeloma cells. , 2014, Blood.

[2]  G. Taraboletti,et al.  Bioavailability of VEGF in tumor-shed vesicles depends on vesicle burst induced by acidic pH. , 2006, Neoplasia.

[3]  G. Calin,et al.  Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B chronic lymphocytic leukemia. , 2013, Blood.

[4]  M. Kuroda,et al.  Leukemia cell to endothelial cell communication via exosomal miRNAs , 2013, Oncogene.

[5]  R. Koch,et al.  ABC transporter A3 facilitates lysosomal sequestration of imatinib and modulates susceptibility of chronic myeloid leukemia cell lines to this drug , 2009, Haematologica.

[6]  Cicek Gercel-Taylor,et al.  MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. , 2008, Gynecologic oncology.

[7]  Veronica Huber,et al.  Recent advances on the role of tumor exosomes in immunosuppression and disease progression. , 2012, Seminars in cancer biology.

[8]  W. Möbius,et al.  Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A–C , 2010, The Journal of cell biology.

[9]  S. Verstovsek,et al.  Role of angiogenesis in chronic lymphocytic leukemia , 2006, Cancer.

[10]  Lin Zhou,et al.  Extracellular vesicle-mediated transfer of donor genomic DNA to recipient cells is a novel mechanism for genetic influence between cells. , 2013, Journal of molecular cell biology.

[11]  D. Lyden,et al.  The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. , 2011, Seminars in cancer biology.

[12]  M. Ringnér,et al.  Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development , 2013, Proceedings of the National Academy of Sciences.

[13]  Yili Yang,et al.  Secretion of annexin A3 from ovarian cancer cells and its association with platinum resistance in ovarian cancer patients , 2012, Journal of cellular and molecular medicine.

[14]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[15]  Aled Clayton,et al.  Adhesion and signaling by B cell‐derived exosomes: the role of integrins , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[16]  George A Calin,et al.  Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. , 2014, Cancer cell.

[17]  Olivier Elemento,et al.  Double-stranded DNA in exosomes: a novel biomarker in cancer detection , 2014, Cell Research.

[18]  Salma Khan,et al.  Extracellular, cell-permeable survivin inhibits apoptosis while promoting proliferative and metastatic potential , 2009, British Journal of Cancer.

[19]  Djuro Josic,et al.  Microvesicle entry into marrow cells mediates tissue-specific changes in mRNA by direct delivery of mRNA and induction of transcription. , 2010, Experimental hematology.

[20]  J. Alam,et al.  Gene microarray analysis reveals a novel hypoxia signal transduction pathway in human hepatocellular carcinoma cells. , 2001, International journal of oncology.

[21]  Marta Di Nicola,et al.  microRNAs Derived from Circulating Exosomes as Noninvasive Biomarkers for Screening and Diagnosing Lung Cancer , 2013, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[22]  Johan Skog,et al.  Glioblastoma microvesicles transport RNA and protein that promote tumor growth and provide diagnostic biomarkers , 2008, Nature Cell Biology.

[23]  Simon C Watkins,et al.  Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. , 2004, Blood.

[24]  A. Maity,et al.  Hypoxia and VEGF mRNA expression in human tumors. , 2001, Neoplasia.

[25]  Jing Li,et al.  Secreted monocytic miR-150 enhances targeted endothelial cell migration. , 2010, Molecular cell.

[26]  J. Lötvall,et al.  Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes , 2013, Journal of extracellular vesicles.

[27]  Michael A. Gibson,et al.  Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells , 2005, Molecular Cancer Therapeutics.

[28]  P. Iversen,et al.  Increased bone marrow microvascular density in haematological malignancies is associated with differential regulation of angiogenic factors , 2009, Leukemia.

[29]  Hamid Cheshmi Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers , 2011 .

[30]  W. Kuo,et al.  Extracellular Vesicles as Shuttles of Tumor Biomarkers and Anti-Tumor Drugs , 2014, Front. Oncol..

[31]  D. Mukhopadhyay,et al.  Circulating microvesicles in B-cell chronic lymphocytic leukemia can stimulate marrow stromal cells: implications for disease progression. , 2010, Blood.

[32]  T. Whiteside,et al.  Plasma Exosomes as Markers of Therapeutic Response in Patients with Acute Myeloid Leukemia , 2014, Front. Immunol..

[33]  Miguel C. Seabra,et al.  Rab27a and Rab27b control different steps of the exosome secretion pathway , 2010, Nature Cell Biology.

[34]  K. Ohyashiki,et al.  Exosomes Derived from Hypoxic Leukemia Cells Enhance Tube Formation in Endothelial Cells* , 2013, The Journal of Biological Chemistry.

[35]  H. Jäck,et al.  Serum microRNAs as powerful cancer biomarkers. , 2010, Biochimica et biophysica acta.

[36]  William C Hines,et al.  Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression , 2011, Nature Medicine.

[37]  J. Ryan,et al.  Exosomal Signaling during Hypoxia Mediates Microvascular Endothelial Cell Migration and Vasculogenesis , 2013, PloS one.

[38]  R. Setterquist,et al.  Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. , 2012, Biochimica et biophysica acta.

[39]  S. Raimondo,et al.  Carboxyamidotriazole-Orotate Inhibits the Growth of Imatinib-Resistant Chronic Myeloid Leukaemia Cells and Modulates Exosomes-Stimulated Angiogenesis , 2012, PloS one.

[40]  Gema Moreno-Bueno,et al.  Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET , 2012, Nature Medicine.

[41]  L. Mincheva-Nilsson,et al.  Thermal- and Oxidative Stress Causes Enhanced Release of NKG2D Ligand-Bearing Immunosuppressive Exosomes in Leukemia/Lymphoma T and B Cells , 2011, PloS one.

[42]  C. Théry,et al.  Membrane vesicles as conveyors of immune responses , 2009, Nature Reviews Immunology.

[43]  A. Guha,et al.  Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells , 2008, Nature Cell Biology.

[44]  A. M. George,et al.  The ABC transporter structure and mechanism: perspectives on recent research , 2004, Cellular and Molecular Life Sciences CMLS.

[45]  Massimo Spada,et al.  High Levels of Exosomes Expressing CD63 and Caveolin-1 in Plasma of Melanoma Patients , 2009, PloS one.

[46]  Jared L. Johnson,et al.  Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells , 2011, Proceedings of the National Academy of Sciences.

[47]  B. Bao,et al.  Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review , 2013, Cancer and Metastasis Reviews.

[48]  D. Scadden,et al.  BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. , 2013, The Journal of clinical investigation.

[49]  K. O'Byrne,et al.  Functions and Therapeutic Roles of Exosomes in Cancer , 2014, Front. Oncol..

[50]  Xiaorong Tan,et al.  Transferred BCR/ABL DNA from K562 Extracellular Vesicles Causes Chronic Myeloid Leukemia in Immunodeficient Mice , 2014, PloS one.

[51]  S. Lim,et al.  Hypoxic Tumor Cell Modulates Its Microenvironment to Enhance Angiogenic and Metastatic Potential by Secretion of Proteins and Exosomes* , 2010, Molecular & Cellular Proteomics.

[52]  Yang Yang,et al.  Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo. , 2012, Stem cells and development.

[53]  F. de Longueville,et al.  Expression profiling of ATP-binding cassette transporters in childhood T-cell acute lymphoblastic leukemia , 2006, Molecular Cancer Therapeutics.

[54]  Crislyn D'Souza-Schorey,et al.  Microvesicles: mediators of extracellular communication during cancer progression , 2010, Journal of Cell Science.

[55]  S. Raimondo,et al.  Exosomes as Intercellular Signaling Organelles Involved in Health and Disease: Basic Science and Clinical Applications , 2013, International journal of molecular sciences.

[56]  C. Roberts,et al.  RNA trafficking by acute myelogenous leukemia exosomes. , 2013, Cancer research.

[57]  Hong-xiang Wang,et al.  Microvesicles secreted from human multiple myeloma cells promote angiogenesis , 2013, Acta Pharmacologica Sinica.

[58]  Peter T. Nelson,et al.  Hypoxia Is Important in the Biology and Aggression of Human Glial Brain Tumors , 2004, Clinical Cancer Research.

[59]  M. T. Damiani,et al.  Rab11 Promotes Docking and Fusion of Multivesicular Bodies in a Calcium‐Dependent Manner , 2005, Traffic.

[60]  Chow H Lee Reversing agents for ATP-binding cassette drug transporters. , 2010, Methods in molecular biology.

[61]  C. Cogle,et al.  Angiogenesis in Acute Myeloid Leukemia and Opportunities for Novel Therapies , 2011, Journal of oncology.

[62]  M. Michael,et al.  Hypoxic enhancement of exosome release by breast cancer cells , 2012, BMC Cancer.

[63]  Z. Fishelson,et al.  Emission of membrane vesicles: roles in complement resistance, immunity and cancer , 2005, Springer Seminars in Immunopathology.

[64]  Sabrina Bonomini,et al.  Angiogenesis and Multiple Myeloma , 2011, Cancer Microenvironment.

[65]  T. Whiteside,et al.  Blast-derived microvesicles in sera from patients with acute myeloid leukemia suppress natural killer cell function via membrane-associated transforming growth factor-β1 , 2011, Haematologica.

[66]  E. Kohn,et al.  Exosomes released by K562 chronic myeloid leukemia cells promote angiogenesis in a src-dependent fashion , 2011, Angiogenesis.

[67]  D. Ribatti,et al.  Insights in Hodgkin Lymphoma angiogenesis. , 2014, Leukemia research.

[68]  Z. Fishelson,et al.  Mortalin/GRP75 promotes release of membrane vesicles from immune attacked cells and protection from complement-mediated lysis. , 2005, International immunology.

[69]  Shant Kumar,et al.  The Role of Endothelial Progenitor Cells in Tumour Vasculogenesis , 2008, Pathobiology.

[70]  J. Brown,et al.  Exploiting tumour hypoxia in cancer treatment , 2004, Nature Reviews Cancer.

[71]  K. Preissner,et al.  Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. , 2010, Cancer research.

[72]  M. Oppermann,et al.  Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3 , 2011, Proceedings of the National Academy of Sciences.

[73]  Jacopo Meldolesi,et al.  Shedding microvesicles: artefacts no more. , 2009, Trends in cell biology.

[74]  A. Russo,et al.  Exosomal shuttling of miR-126 in endothelial cells modulates adhesive and migratory abilities of chronic myelogenous leukemia cells , 2014, Molecular Cancer.

[75]  P. Ricciardi-Castagnoli,et al.  Proteomic Analysis of Dendritic Cell-Derived Exosomes: A Secreted Subcellular Compartment Distinct from Apoptotic Vesicles1 , 2001, The Journal of Immunology.

[76]  L. Coussens,et al.  Paradoxical roles of the immune system during cancer development , 2006, Nature Reviews Cancer.

[77]  A. Falus,et al.  Highlights of a new type of intercellular communication: microvesicle-based information transfer , 2009, Inflammation Research.

[78]  N. Cheong,et al.  Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration , 2008, Leukemia.

[79]  K. Ohyashiki,et al.  Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. , 2014, Blood.

[80]  C. Melief,et al.  B lymphocytes secrete antigen-presenting vesicles , 1996, The Journal of experimental medicine.

[81]  S. Raimondo,et al.  Exosome-mediated crosstalk between chronic myelogenous leukemia cells and human bone marrow stromal cells triggers an interleukin 8-dependent survival of leukemia cells. , 2014, Cancer letters.

[82]  H R Büller,et al.  Cell-derived microvesicles and cancer. , 2009, The Netherlands journal of medicine.

[83]  E. Kohn,et al.  Role of exosomes released by chronic myelogenous leukemia cells in angiogenesis , 2012, International journal of cancer.

[84]  L. Zitvogel,et al.  Malignant effusions and immunogenic tumour-derived exosomes , 2002, The Lancet.

[85]  T. Deguchi,et al.  Isolation of prostate cancer-related exosomes. , 2014, Anticancer research.

[86]  J. Sixma,et al.  Activated Platelets Release Two Types of Membrane Vesicles: Microvesicles by Surface Shedding and Exosomes Derived From Exocytosis of Multivesicular Bodies and -Granules , 1999 .

[87]  Ylva Ivarsson,et al.  Syndecan–syntenin–ALIX regulates the biogenesis of exosomes , 2012, Nature Cell Biology.