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

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Christianson, HelenaLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine (författare)

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

Artikel/kapitelEngelska2013

Förlag, utgivningsår, omfång ...

2013-10-07
Proceedings of the National Academy of Sciences,2013
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LIBRIS-ID:oai:DiVA.org:uu-211450
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-211450URI
https://doi.org/10.1073/pnas.1304266110DOI
https://lup.lub.lu.se/record/4143585URI

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Språk:engelska
Sammanfattning på:engelska

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Ämneskategori:art swepub-publicationtype

Anmärkningar

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.

Ämnesord och genrebeteckningar

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Cancer och onkologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cancer and Oncology hsv//eng
endocytosis
tumor
glioma

Biuppslag (personer, institutioner, konferenser, titlar ...)

Svensson, KatrinLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)med-ksv (författare)
van Kuppevelt, Toin H. (författare)
Li, Jin-PingUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi(Swepub:uu)jinpili (författare)
Belting, MattiasLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)medk-mbe (författare)
Bröstcancer-genetikSektion I (creator_code:org_t)

Sammanhörande titlar

Ingår i:Proceedings of the National Academy of Sciences of the United States of America: Proceedings of the National Academy of Sciences110:43, s. 17380-173850027-84241091-6490

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Av författaren/redakt...: Christianson, He ...; Svensson, Katrin; van Kuppevelt, T ...; Li, Jin-Ping; Belting, Mattias

Om ämnet

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Cancer och onkol ...

Artiklar i publikationen: Proceedings of t ...

Av lärosätet: Uppsala universitet; Lunds universitet

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