Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development.
Kucharzewska, Paulina LU ; Christianson, Helena LU ; Welch, Johanna LU ; Svensson, Katrin LU ; Fredlund, Erik LU ; Ringnér, Markus LU
; Mörgelin, Matthias
LU
; Bourseau-Guilmain, Erika
LU
; Bengzon, Johan
LU
and Belting, Mattias
LU
(2013)
In Proceedings of the National Academy of Sciences
110(18).
p.7312-7317
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3733733
- author
- Kucharzewska, Paulina
LU
; Christianson, Helena
LU
; Welch, Johanna
LU
; Svensson, Katrin
LU
; Fredlund, Erik
LU
; Ringnér, Markus
LU
; Mörgelin, Matthias
LU
; Bourseau-Guilmain, Erika
LU
; Bengzon, Johan
LU
and Belting, Mattias
LU
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Proceedings of the National Academy of Sciences
- volume
- 110
- issue
- 18
- pages
- 7312 - 7317
- publisher
- National Academy of Sciences
- external identifiers
-
- wos:000318682300049
- pmid:23589885
- scopus:84876927914
- pmid:23589885
- ISSN
- 1091-6490
- DOI
- 10.1073/pnas.1220998110
- language
- English
- LU publication?
- yes
- id
- 0ff62716-a15e-4efa-9b02-976bf13c4fc4 (old id 3733733)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/23589885?dopt=Abstract
- date added to LUP
- 2016-04-01 10:38:47
- date last changed
- 2022-04-27 23:48:51
@article{0ff62716-a15e-4efa-9b02-976bf13c4fc4,
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.}},
author = {{Kucharzewska, Paulina and Christianson, Helena and Welch, Johanna and Svensson, Katrin and Fredlund, Erik and Ringnér, Markus and Mörgelin, Matthias and Bourseau-Guilmain, Erika and Bengzon, Johan and Belting, Mattias}},
issn = {{1091-6490}},
language = {{eng}},
number = {{18}},
pages = {{7312--7317}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences}},
title = {{Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development.}},
url = {{http://dx.doi.org/10.1073/pnas.1220998110}},
doi = {{10.1073/pnas.1220998110}},
volume = {{110}},
year = {{2013}},
}