title: Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development.
abstract: Hypoxia, or low oxygen tension, is a major regulator of tumor development and aggressiveness. However, how cancer cells adapt to hypoxia and communicate with their surrounding microenvironment during tumor development remain important questions. Here, we show that secreted vesicles with exosome characteristics mediate hypoxia-dependent intercellular signaling of the highly malignant brain tumor glioblastoma multiforme (GBM). In vitro hypoxia experiments with glioma cells and studies with patient materials reveal the enrichment in exosomes of hypoxia-regulated mRNAs and proteins (e.g., matrix metalloproteinases, IL-8, PDGFs, caveolin 1, and lysyl oxidase), several of which were associated with poor glioma patient prognosis. We show that exosomes derived from GBM cells grown at hypoxic compared with normoxic conditions are potent inducers of angiogenesis ex vivo and in vitro through phenotypic modulation of endothelial cells. Interestingly, endothelial cells were programmed by GBM cell-derived hypoxic exosomes to secrete several potent growth factors and cytokines and to stimulate pericyte PI3K/AKT signaling activation and migration. Moreover, exosomes derived from hypoxic compared with normoxic conditions showed increased autocrine, promigratory activation of GBM cells. These findings were correlated with significantly enhanced induction by hypoxic compared with normoxic exosomes of tumor vascularization, pericyte vessel coverage, GBM cell proliferation, as well as decreased tumor hypoxia in a mouse xenograft model. We conclude that the proteome and mRNA profiles of exosome vesicles closely reflect the oxygenation status of donor glioma cells and patient tumors, and that the exosomal pathway constitutes a potentially targetable driver of hypoxia-dependent intercellular signaling during tumor development.
authors.affiliation: Department of Clinical Sciences, Section of Oncology, Lund University, SE-221 85 Lund, Sweden.
authors.forename: Paulina
authors.initials: P
authors.lastname: Kucharzewska
authors.forename: Helena C
authors.initials: HC
authors.lastname: Christianson
authors.forename: Johanna E
authors.initials: JE
authors.lastname: Welch
authors.forename: Katrin J
authors.initials: KJ
authors.lastname: Svensson
authors.forename: Erik
authors.initials: E
authors.lastname: Fredlund
authors.forename: Markus
authors.initials: M
authors.lastname: Ringnér
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Erika
authors.initials: E
authors.lastname: Bourseau-Guilmain
authors.forename: Johan
authors.initials: J
authors.lastname: Bengzon
authors.forename: Mattias
authors.initials: M
authors.lastname: Belting
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001808:Blood Vessels / Q000473:pathology*; D001932:Brain Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology*; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000098:blood supply* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D019899:Paracrine Communication; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D020543:Proteome / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014019:Tissue Donors; D059467:Transcriptome / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D009363:Neoplasm Proteins; D020543:Proteome