title: Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts.
abstract: Exosomes derived from solid tumor cells are involved in immune suppression, angiogenesis, and metastasis, but the role of leukemia-derived exosomes has been less investigated. The pathogenesis of chronic lymphocytic leukemia (CLL) is stringently associated with a tumor-supportive microenvironment and a dysfunctional immune system. Here, we explore the role of CLL-derived exosomes in the cellular and molecular mechanisms by which malignant cells create this favorable surrounding. We show that CLL-derived exosomes are actively incorporated by endothelial and mesenchymal stem cells ex vivo and in vivo and that the transfer of exosomal protein and microRNA induces an inflammatory phenotype in the target cells, which resembles the phenotype of cancer-associated fibroblasts (CAFs). As a result, stromal cells show enhanced proliferation, migration, and secretion of inflammatory cytokines, contributing to a tumor-supportive microenvironment. Exosome uptake by endothelial cells increased angiogenesis ex vivo and in vivo, and coinjection of CLL-derived exosomes and CLL cells promoted tumor growth in immunodeficient mice. Finally, we detected α-smooth actin-positive stromal cells in lymph nodes of CLL patients. These findings demonstrate that CLL-derived exosomes actively promote disease progression by modulating several functions of surrounding stromal cells that acquire features of cancer-associated fibroblasts.
authors.affiliation: Laboratory of Experimental Hemato-Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg;
authors.forename: Jerome
authors.initials: J
authors.lastname: Paggetti
authors.affiliation: Department for Molecular Genetics, German Cancer Research Center, Heidelberg, Germany;
authors.forename: Franziska
authors.initials: F
authors.lastname: Haderk
authors.affiliation: Department for Molecular Genetics, German Cancer Research Center, Heidelberg, Germany;
authors.forename: Martina
authors.initials: M
authors.lastname: Seiffert
authors.affiliation: Laboratory of Experimental Hemato-Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg;
authors.forename: Bassam
authors.initials: B
authors.lastname: Janji
authors.affiliation: Luxembourg Clinical Proteomics Center, Luxembourg Institute of Health, Luxembourg, Luxembourg;
authors.forename: Ute
authors.initials: U
authors.lastname: Distler
authors.affiliation: Integrated BioBank of Luxembourg, Luxembourg, Luxembourg;
authors.forename: Wim
authors.initials: W
authors.lastname: Ammerlaan
authors.affiliation: Luxembourg Clinical Proteomics Center, Luxembourg Institute of Health, Luxembourg, Luxembourg;
authors.forename: Yeoun Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: INSERM U981, Gustave Roussy, Villejuif, France; Faculty of Medicine, University Paris-Sud, Le Kremlin-Bicêtre, France;
authors.forename: Julien
authors.initials: J
authors.lastname: Adam
authors.affiliation: Department for Molecular Genetics, German Cancer Research Center, Heidelberg, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.affiliation: Faculty of Medicine, University Paris-Sud, Le Kremlin-Bicêtre, France; INSERM UMR1009, Gustave Roussy Villejuif, France; and.
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.affiliation: Laboratory of Experimental Hemato-Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg; Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg.
authors.forename: Guy
authors.initials: G
authors.lastname: Berchem
authors.affiliation: Laboratory of Experimental Hemato-Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg;
authors.forename: Etienne
authors.initials: E
authors.lastname: Moussay
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002470:Cell Survival; D002478:Cells, Cultured; D055354:Exosomes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D015398:Signal Transduction; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
chemical_list: D035683:MicroRNAs