TY - JOUR
T1 - Reactive astrocytic S1P3 signaling modulates the blood-tumor barrier in brain metastases
AU - Gril, Brunilde
AU - Paranjape, Anurag N.
AU - Woditschka, Stephan
AU - Hua, Emily
AU - Dolan, Emma L.
AU - Hanson, Jeffrey
AU - Wu, Xiaolin
AU - Kloc, Wojciech
AU - Izycka-Swieszewska, Ewa
AU - Duchnowska, Renata
AU - Pȩksa, Rafał
AU - Biernat, Wojciech
AU - Jassem, Jacek
AU - Nayyar, Naema
AU - Brastianos, Priscilla K.
AU - Hall, O. Morgan
AU - Peer, Cody J.
AU - Figg, William D.
AU - Pauly, Gary T.
AU - Robinson, Christina
AU - Difilippantonio, Simone
AU - Bialecki, Emilie
AU - Metellus, Philippe
AU - Schneider, Joel P.
AU - Steeg, Patricia S.
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85049926815&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-05030-w
DO - 10.1038/s41467-018-05030-w
M3 - Article
C2 - 30006619
AN - SCOPUS:85049926815
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2705
ER -