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 - Funding Information:
Competing interests: The authors declare the following competing interests: P.K. Brastianos reports receiving speaker’s bureau honoraria from Genentech and Merck, and is a consultant/advisory board member for Genentech. P.S. Steeg reports receiving a commercial research grant from Genentech and Medimmune. R. Duchnowska reports consulting personal fees from Roche, GSK, Novartis, Lilly, Pfizer, AstraZeneca, Amgen, Boehringer Ingelheim, Teva, and Egis. The other authors declare no competing interests.
Funding Information:
The authors acknowledge the statistical advice of Dr. Seth Steinberg and Mr. David Liewher, Biostatistics and Data Management Section, CCR, NCI, Bethesda, MD, USA. This work was supported by the Intramural program of the National Cancer Institute, U.
Funding Information:
The authors acknowledge the statistical advice of Dr. Seth Steinberg and Mr. David Liewher, Biostatistics and Data Management Section, CCR, NCI, Bethesda, MD, USA. This work was supported by the Intramural program of the National Cancer Institute, U. S. Department of Defense Breast Cancer Research Program, grant number: W81 XWH-062-0033, and a research grant from the Inflammatory Breast Cancer Foundation. The human tissue samples from France were provided by AP-HM tumor bank AC-2013-1786, BB-0033-00097. The immunohistochemistry of human tissue samples performed in Poland was partly funded by the Institutional Grant ST-23 from the Medical University of Gdansk. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Frederick National Laboratory is accredited by AAALAC International and follows the Public Health Service Policy for the Care and Use of Laboratory Animals. Animal care was provided in accordance with the procedures outlined in the "Guide for Care and Use of Laboratory Animals" (National Research Council; 2011; National Academies Press; Washington, D.C., USA).
Funding Information:
S. Department of Defense Breast Cancer Research Program, grant number: W81 XWH-062-0033, and a research grant from the Inflammatory Breast Cancer Foundation. The human tissue samples from France were provided by AP-HM tumor bank AC-2013-1786, BB-0033-00097. The immunohistochemistry of human tissue samples performed in Poland was partly funded by the Institutional Grant ST-23 from the Medical University of Gdańsk. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Frederick National Laboratory is accredited by AAALAC International and follows the Public Health Service Policy for the Care and Use of Laboratory Animals. Animal care was provided in accordance with the procedures outlined in the “Guide for Care and Use of Laboratory Animals” (National Research Council; 2011; National Academies Press; Washington, D.C., USA).
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 -