Evidence map›Paper›PMID 24101524›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2013

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

Helena C Christianson, Katrin J Svensson, Toin H van Kuppevelt, Jin-Ping Li, Mattias Belting

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PubMed Full text at PMC Publisher
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 526 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
526citing papers in PubMed, 1 pooled it
22.3field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

526 citing papers in PubMed, 1 synthesis or guideline pooled it, 852 citations in OpenAlex.

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466 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

5 authors at 4 institutions in 2 countries.

Helena C ChristiansonDepartment of Clinical Sciences, Section of Oncology, Lund University, SE-221 85 Lund, Sweden.
Katrin J Svensson
Toin H van Kuppevelt
Jin-Ping Li
Mattias Belting
Lund University · SERadboud University Medical Center · NLSkåne University Hospital · SEUppsala University · SE

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

EndocytosisAnimalsBlotting, WesternCell Line, TumorCell MembraneCHO CellsCricetinaeCricetulusCytoplasmDose-Response Relationship, DrugExosomesFlow CytometryGlycosidesHeparan SulfateHeparan Sulfate ProteoglycansHumansGlycosidesHeparan SulfateHeparan Sulfate ProteoglycansMAPK1 protein, humanMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3xylosidesendocytosisgliomatumor

Identifiers

PMID24101524
PMCPMC3808637
OpenAlexW2008627178

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.