Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8

被引：80

作者：

Berenguer, Jordi ^{[1
]}

Lagerweij, Tonny ^{[1
]}

Zhao, Xi Wen ^{[1
]}

Dusoswa, Sophie ^{[2
]}

van der Stoop, Petra ^{[1
]}

Westerman, Bart ^{[1
]}

de Gooijer, Mark C. ^{[3
]}

Zoetemelk, Marloes ^{[1
]}

Zomer, Anoek ^{[4
,5
]}

Crommentuijn, Matheus H. W. ^{[1
,3
,6
,7
]}

Wedekind, Laurine E. ^{[1
]}

Lopez-Lopez, Alan ^{[8
]}

Giovanazzi, Alberta ^{[1
]}

Bruch-Oms, Marina ^{[2
]}

van der Meulen-Muileman, Ida H. ^{[9
]}

Reijmers, Rogier M. ^{[2
]}

van Kuppevelt, Toin H. ^{[10
]}

Garcia-Vallejo, Juan-Jesus ^{[2
]}

van Kooyk, Yvette ^{[2
]}

Tannous, Bakhos A. ^{[6
,7
]}

Wesseling, Pieter ^{[11
,12
,13
]}

Koppers-Lalic, Danijela ^{[1
]}

Vandertop, W. Peter ^{[1
]}

Noske, David P. ^{[1
]}

van Beusechem, Victor W. ^{[9
]}

van Rheenen, Jacco ^{[4
,5
]}

Pegtel, D. Michiel ^{[10
]}

van Tellingen, Olaf ^{[3
]}

Wurdinger, Thomas ^{[1
,6
,7
]}

机构：

[1] Vrije Univ Amsterdam Med Ctr, Dept Neurosurg, De Boelelaan 1118, NL-1081 HV Amsterdam, Netherlands

[2] Vrije Univ Amsterdam Med Ctr, Dept Mol Cell Biol & Immunol, Amsterdam, Netherlands

[3] Netherlands Canc Inst, Mouse Canc Clin, Dept Biopharm, Amsterdam, Netherlands

[4] Hubrecht Inst KNAW, Canc Genom Netherlands, Utrecht, Netherlands

[5] Univ Med Ctr Utrecht, Utrecht, Netherlands

[6] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[7] Harvard Med Sch, Program Neurosci, Boston, MA USA

[8] Univ Barcelona, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Dept Physiol Sci 1, Barcelona, Spain

[9] Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, Amsterdam, Netherlands

[10] Radboud Univ Nijmegen, Med Ctr, Dept Matrix Biochem, Nijmegen, Netherlands

[11] Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands

[12] Princess Maxima Ctr Pediat Oncol, Dept Pathol, Utrecht, Netherlands

[13] Univ Med Ctr Utrecht, Utrecht, Netherlands

来源：

JOURNAL OF EXTRACELLULAR VESICLES | 2018年 / 7卷 / 01期

基金：

欧洲研究理事会;

关键词：

Extracellular vesicles; glioblastoma; Chemokine receptor; CCR8; therapy resistance; temozolomide; RNAi screening; glycans; IMMUNODEFICIENCY-VIRUS TYPE-1; TEMOZOLOMIDE RESISTANCE; INTERCELLULAR TRANSFER; MEDIATED TRANSFER; BREAST-CANCER; EXOSOMES; IDENTIFICATION; MICROVESICLES; EXPRESSION; PATHWAY;

D O I：

10.1080/20013078.2018.1446660

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Cancer cells release extracellular vesicles (EVs) that contain functional biomolecules such as RNA and proteins. EVs are transferred to recipient cancer cells and can promote tumour progression and therapy resistance. Through RNAi screening, we identified a novel EV uptake mechanism involving a triple interaction between the chemokine receptor CCR8 on the cells, glycans exposed on EVs and the soluble ligand CCL18. This ligand acts as bridging molecule, connecting EVs to cancer cells. We show that glioblastoma EVs promote cell proliferation and resistance to the alkylating agent temozolomide (TMZ). Using in vitro and in vivo stem-like glioblastoma models, we demonstrate that EV-induced phenotypes are neutralised by a small molecule CCR8 inhibitor, R243. Interference with chemokine receptors may offer therapeutic opportunities against EV-mediated cross-talk in glioblastoma.

引用

页数：21

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