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

Author

Listed:
  • Brunilde Gril

    (CCR, NCI)

  • Anurag N. Paranjape

    (CCR, NCI)

  • Stephan Woditschka

    (CCR, NCI
    University of North Carolina at Wilmington)

  • 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
    Copernicus Hospital Gdańsk)

  • Ewa Izycka-Swieszewska

    (Medical University of Gdańsk
    Copernicus Hospital 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
    Aix-Marseille Université)

  • Joel P. Schneider

    (CCR, NCI)

  • Patricia S. Steeg

    (CCR, NCI)

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.

Suggested Citation

  • 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, 2018. "Reactive astrocytic S1P3 signaling modulates the blood–tumor barrier in brain metastases," Nature Communications, Nature, vol. 9(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05030-w
    DOI: 10.1038/s41467-018-05030-w
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    Cited by:

    1. Weili Ma & Maria Cecília Oliveira-Nunes & Ke Xu & Andrew Kossenkov & Benjamin C. Reiner & Richard C. Crist & James Hayden & Qing Chen, 2023. "Type I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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