Reactive astrocytic S1P3 signaling modulates the blood–tumor barrier in brain metastases

Brunilde Gril (), Anurag N. Paranjape, Stephan Woditschka, Emily Hua, Emma L. Dolan, Jeffrey Hanson, Xiaolin Wu, Wojciech Kloc, Ewa Izycka-Swieszewska, Renata Duchnowska, Rafał Pęksa, Wojciech Biernat, Jacek Jassem, Naema Nayyar, Priscilla K. Brastianos, O. Morgan Hall, Cody J. Peer, William D. Figg, Gary T. Pauly, Christina Robinson, Simone Difilippantonio, Emilie Bialecki, Philippe Metellus, Joel P. Schneider and Patricia S. Steeg ()
Additional contact information
Brunilde Gril: CCR, NCI
Anurag N. Paranjape: CCR, NCI
Stephan Woditschka: CCR, NCI
Emily Hua: CCR, NCI
Emma L. Dolan: CCR, NCI
Jeffrey Hanson: CCR, NCI
Xiaolin Wu: Frederick National Laboratory for Cancer Research
Wojciech Kloc: Varmia & Masuria University
Ewa Izycka-Swieszewska: Medical University of Gdańsk
Renata Duchnowska: Military Institute of Medicine
Rafał Pęksa: Medical University of Gdańsk
Wojciech Biernat: Medical University of Gdańsk
Jacek Jassem: Medical University of Gdańsk
Naema Nayyar: Harvard Medical School
Priscilla K. Brastianos: Harvard Medical School
O. Morgan Hall: CCR, NCI
Cody J. Peer: CCR, NCI
William D. Figg: CCR, NCI
Gary T. Pauly: CCR, NCI
Christina Robinson: Frederick National Laboratory for Cancer Research
Simone Difilippantonio: Frederick National Laboratory for Cancer Research
Emilie Bialecki: Hôpital Privé Clairval, Ramsay Général de Santé
Philippe Metellus: Hôpital Privé Clairval, Ramsay Général de Santé
Joel P. Schneider: CCR, NCI
Patricia S. Steeg: CCR, NCI

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: Abstract Brain metastases are devastating complications of cancer. The blood–brain barrier (BBB), which protects the normal brain, morphs into an inadequately characterized blood–tumor barrier (BTB) when brain metastases form, and is surrounded by a neuroinflammatory response. These structures contribute to poor therapeutic efficacy by limiting drug uptake. Here, we report that experimental breast cancer brain metastases of low- and high permeability to a dextran dye exhibit distinct microenvironmental gene expression patterns. Astrocytic sphingosine-1 phosphate receptor 3 (S1P3) is upregulated in the neuroinflammatory response of the highly permeable lesions, and is expressed in patients’ brain metastases. S1P3 inhibition functionally tightens the BTB in vitro and in vivo. S1P3 mediates its effects on BTB permeability through astrocytic secretion of IL-6 and CCL2, which relaxes endothelial cell adhesion. Tumor cell overexpression of S1P3 mimics this pathway, enhancing IL-6 and CCL-2 production and elevating BTB permeability. In conclusion, neuroinflammatory astrocytic S1P3 modulates BTB permeability.

Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-018-05030-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05030-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-05030-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().