Journal Article

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

Izycka-Swieszewska, Ewa, Nayyar, Naema, Hua, Emily, Biernat, Wojciech, Wu, Xiaolin, Peer, Cody J., Gril, Brunilde, Duchnowska, Renata, Bialecki, Emilie, Pęksa, Rafał, Difilippantonio, Simone, Schneider, Joel P., Steeg, Patricia S., Dolan, Emma L., Metellus, Philippe, Jassem, Jacek, Pauly, Gary T., Figg, William D., Hanson, Jeffrey, Paranjape, Anurag N., Woditschka, Stephan, Robinson, Christina, Kloc, Wojciech, Brastianos, Priscilla K., Hall, O. Morgan

2018

Overview

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. When brain metastases form, the blood–brain barrier morphs into the blood–tumor barrier (BTB), surrounded by neuroinflammatory response. Here, the authors show that S1P3 is upregulated in neuroinflammatory response in highly BTB permeable lesions, and modulation of S1P3 could impact BTB permeability.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/109 / 13/21 / 13/89 / 13/95 / 14/19 / 14/34 / 14/63 / 38/61 / 631/378/1341 / 631/67/1347 / 631/67/322 / Animals / Antibiotics, Antineoplastic - pharmacokinetics / Antibiotics, Antineoplastic - pharmacology / Astrocytes - metabolism / Astrocytes - pathology / Blood-brain barrier / Blood-Brain Barrier - metabolism / Blood-Brain Barrier - pathology / Brain cancer / Brain Neoplasms - drug therapy / Brain Neoplasms - genetics / Brain Neoplasms - metabolism / Brain Neoplasms - secondary / Brain tumors / Breast cancer / Cancer / Cell adhesion / Cell adhesion & migration / Cell Line, Tumor / Chemokine CCL2 - genetics / Chemokine CCL2 - metabolism / Dextran / Doxorubicin - pharmacokinetics / Doxorubicin - pharmacology / Endothelial cells / Female / Fluorescent Dyes - chemistry / Fluorescent Dyes - pharmacology / Gene expression / Gene Expression Regulation, Neoplastic / Humanities and Social Sciences / Humans / Inflammation / Injections, Intramuscular / Interleukin 6 / Interleukin-6 - genetics / Interleukin-6 - metabolism / Lesions / Metastases / Metastasis / Mice, Nude / Monocyte chemoattractant protein 1 / multidisciplinary / Myocardium / Permeability / Receptors, Lysosphingolipid - genetics / Receptors, Lysosphingolipid - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Toxicity / Triple Negative Breast Neoplasms - drug therapy / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - metabolism / Triple Negative Breast Neoplasms - pathology / Tumors / Xanthenes - chemistry / Xanthenes - metabolism