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Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity.

Christianson, Helena LU ; Svensson, Katrin LU ; van Kuppevelt, Toin H ; Li, Jin-Ping and Belting, Mattias LU (2013) In Proceedings of the National Academy of Sciences 110(43). p.17380-17385
Abstract
Extracellular vesicle (EV)-mediated intercellular transfer of signaling proteins and nucleic acids has recently been implicated in the development of cancer and other pathological conditions; however, the mechanism of EV uptake and how this may be targeted remain as important questions. Here, we provide evidence that heparan sulfate (HS) proteoglycans (PGs; HSPGs) function as internalizing receptors of cancer cell-derived EVs with exosome-like characteristics. Internalized exosomes colocalized with cell-surface HSPGs of the syndecan and glypican type, and exosome uptake was specifically inhibited by free HS chains, whereas closely related chondroitin sulfate had no effect. By using several cell mutants, we provide genetic evidence of a... (More)
Extracellular vesicle (EV)-mediated intercellular transfer of signaling proteins and nucleic acids has recently been implicated in the development of cancer and other pathological conditions; however, the mechanism of EV uptake and how this may be targeted remain as important questions. Here, we provide evidence that heparan sulfate (HS) proteoglycans (PGs; HSPGs) function as internalizing receptors of cancer cell-derived EVs with exosome-like characteristics. Internalized exosomes colocalized with cell-surface HSPGs of the syndecan and glypican type, and exosome uptake was specifically inhibited by free HS chains, whereas closely related chondroitin sulfate had no effect. By using several cell mutants, we provide genetic evidence of a receptor function of HSPG in exosome uptake, which was dependent on intact HS, specifically on the 2-O and N-sulfation groups. Further, enzymatic depletion of cell-surface HSPG or pharmacological inhibition of endogenous PG biosynthesis by xyloside significantly attenuated exosome uptake. We provide biochemical evidence that HSPGs are sorted to and associate with exosomes; however, exosome-associated HSPGs appear to have no direct role in exosome internalization. On a functional level, exosome-induced ERK1/2 signaling activation was attenuated in PG-deficient mutant cells as well as in WT cells treated with xyloside. Importantly, exosome-mediated stimulation of cancer cell migration was significantly reduced in PG-deficient mutant cells, or by treatment of WT cells with heparin or xyloside. We conclude that cancer cell-derived exosomes use HSPGs for their internalization and functional activity, which significantly extends the emerging role of HSPGs as key receptors of macromolecular cargo. (Less)
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published
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in
Proceedings of the National Academy of Sciences
volume
110
issue
43
pages
17380 - 17385
publisher
National Acad Sciences
external identifiers
  • wos:000325943300052
  • pmid:24101524
  • scopus:84886387008
  • pmid:24101524
ISSN
1091-6490
DOI
10.1073/pnas.1304266110
language
English
LU publication?
yes
id
473644fe-f2c9-4e89-9bd1-61438be5eb93 (old id 4143585)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24101524?dopt=Abstract
date added to LUP
2016-04-01 10:07:28
date last changed
2020-02-19 01:11:12
@article{473644fe-f2c9-4e89-9bd1-61438be5eb93,
  abstract     = {Extracellular vesicle (EV)-mediated intercellular transfer of signaling proteins and nucleic acids has recently been implicated in the development of cancer and other pathological conditions; however, the mechanism of EV uptake and how this may be targeted remain as important questions. Here, we provide evidence that heparan sulfate (HS) proteoglycans (PGs; HSPGs) function as internalizing receptors of cancer cell-derived EVs with exosome-like characteristics. Internalized exosomes colocalized with cell-surface HSPGs of the syndecan and glypican type, and exosome uptake was specifically inhibited by free HS chains, whereas closely related chondroitin sulfate had no effect. By using several cell mutants, we provide genetic evidence of a receptor function of HSPG in exosome uptake, which was dependent on intact HS, specifically on the 2-O and N-sulfation groups. Further, enzymatic depletion of cell-surface HSPG or pharmacological inhibition of endogenous PG biosynthesis by xyloside significantly attenuated exosome uptake. We provide biochemical evidence that HSPGs are sorted to and associate with exosomes; however, exosome-associated HSPGs appear to have no direct role in exosome internalization. On a functional level, exosome-induced ERK1/2 signaling activation was attenuated in PG-deficient mutant cells as well as in WT cells treated with xyloside. Importantly, exosome-mediated stimulation of cancer cell migration was significantly reduced in PG-deficient mutant cells, or by treatment of WT cells with heparin or xyloside. We conclude that cancer cell-derived exosomes use HSPGs for their internalization and functional activity, which significantly extends the emerging role of HSPGs as key receptors of macromolecular cargo.},
  author       = {Christianson, Helena and Svensson, Katrin and van Kuppevelt, Toin H and Li, Jin-Ping and Belting, Mattias},
  issn         = {1091-6490},
  language     = {eng},
  number       = {43},
  pages        = {17380--17385},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity.},
  url          = {http://dx.doi.org/10.1073/pnas.1304266110},
  doi          = {10.1073/pnas.1304266110},
  volume       = {110},
  year         = {2013},
}