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Nat Commun. 2018 Jul 13;9(1):2705. doi: 10.1038/s41467-018-05030-w.

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

Author information

1
Women's Malignancies Branch, CCR, NCI, Bethesda, 20892, MD, USA. grilbrun@mail.nih.gov.
2
Women's Malignancies Branch, CCR, NCI, Bethesda, 20892, MD, USA.
3
Department of Biology and Marine Biology, University of North Carolina at Wilmington, 601 South College Road, Wilmington, NC, 28403, USA.
4
Laboratory of Pathology, CCR, NCI, Bethesda, 20892, MD, USA.
5
Genomics Laboratory, Frederick National Laboratory for Cancer Research, Frederick, 21702, MD, USA.
6
Department of Neurology & Neurosurgery, Varmia & Masuria University, Olsztyn, 10-719, Poland.
7
Department of Neurosurgery, Copernicus Hospital Gdańsk, Gdańsk, 80-803, Poland.
8
Department of Pathology & Neuropathology, Medical University of Gdańsk, Gdańsk, 80-210, Poland.
9
Department of Pathomorphology, Copernicus Hospital Gdańsk, Gdańsk, 80-803, Poland.
10
Department of Oncology, Military Institute of Medicine, Warsaw, 04-141, Poland.
11
Department of Pathology, Medical University of Gdańsk, 7 Dębinki St, 80-211, Gdańsk, Poland.
12
Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, 80-211, Poland.
13
Division of Neuro-Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, 02114, MA, USA.
14
Genitourinary Malignancies Branch, CCR, NCI, Bethesda, 20892, MD, USA.
15
Chemical Biology Laboratory, CCR, NCI, Frederick, 21702, MD, USA.
16
Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, 21702, MD, USA.
17
Département de Neurochirurgie, Hôpital Privé Clairval, Ramsay Général de Santé, Marseille, 13009, France.
18
Institut de Neurophysiopathologie-UMR 7051, Aix-Marseille Université, Marseille, 13344, France.
19
Women's Malignancies Branch, CCR, NCI, Bethesda, 20892, MD, USA. steegp@mail.nih.gov.

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.

PMID:
30006619
PMCID:
PMC6045677
DOI:
10.1038/s41467-018-05030-w
[Indexed for MEDLINE]
Free PMC Article

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