title: Multiple myeloma exosomes establish a favourable bone marrow microenvironment with enhanced angiogenesis and immunosuppression.
abstract: Multiple myeloma (MM) pathogenesis and progression largely rely on the cells and extracellular factors in the bone marrow (BM) microenvironment. Compelling studies have identified tumour exosomes as key regulators in the maintenance and education of the BM microenvironment by targeting stromal cells, immune cells, and vascular cells. However, the role of MM exosomes in the modification of the BM microenvironment and MM progression remains unclear. Here, we explored the functions of MM exosomes in angiogenesis and immunosuppression in vitro and in vivo. Murine MM exosomes carrying multiple angiogenesis-related proteins enhanced angiogenesis and directly promoted endothelial cell growth. Several pathways such as signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase, and p53 were modulated by the exosomes in endothelial and BM stromal cells. These exosomes promoted the growth of myeloid-derived suppressor cells (MDSCs) in naive mice through activation of the STAT3 pathway and changed their subsets to similar phenotypes to those seen in MM-bearing mice. Moreover, MM exosomes up-regulated inducible nitric oxide synthase and enhanced the immunosuppressive capacity of BM MDSCs in vivo. Our data show that MM exosomes modulate the BM microenvironment through enhancement of angiogenesis and immunosuppression, which will further facilitate MM progression. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussels (VUB), Brussels, Belgium.
authors.forename: Jinheng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussels (VUB), Brussels, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: De Veirman
authors.affiliation: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussels (VUB), Brussels, Belgium.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Faict
authors.affiliation: Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: Frassanito
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.|National Cancer Institute 'Giovanni Paolo II', Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.affiliation: Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Vacca
authors.affiliation: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussels (VUB), Brussels, Belgium.
authors.forename: Eline
authors.initials: E
authors.lastname: Menu
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D060833:Cellular Microenvironment; D004195:Disease Models, Animal; D018450:Disease Progression; D055354:Exosomes / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology / Q000473:pathology; D009389:Neovascularization, Pathologic; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; D052247:Nitric Oxide Synthase Type II; D048031:JNK Mitogen-Activated Protein Kinases
keywords: STAT3; angiogenesis; exosomes; immunosuppression; multiple myeloma; myeloid-derived suppressor cells