Metastatic Brain Tumors Disrupt the Blood-Brain Barrier and Alter Lipid Metabolism by Inhibiting Expression of the Endothelial Cell Fatty Acid Transporter Mfsd2a

Autor:	Ganesh Rao, Frederick F. Lang, John E. Morales, Joseph H. McCarty, Sam C. Kwiatkowski, Shweta Tiwary
Jazyk:	angličtina
Rok vydání:	2018
Předmět:	Male 0301 basic medicine lcsh:Medicine Mice Mice Inbred NOD Tumor Microenvironment Neoplasm Metastasis lcsh:Science Multidisciplinary Symporters Brain Neoplasms Chemistry Fatty Acids Brain Fatty Acid Transport Proteins 3. Good health Endothelial stem cell medicine.anatomical_structure Blood-Brain Barrier cardiovascular system Female Signal Transduction Docosahexaenoic Acids Endothelium Brain tumor Mice Nude Blood–brain barrier Article 03 medical and health sciences medicine Animals Humans Tumor microenvironment Ion Transport Tumor Suppressor Proteins lcsh:R Endothelial Cells Membrane Transport Proteins Biological Transport Lipid metabolism Lipid Metabolism medicine.disease Xenograft Model Antitumor Assays Mice Inbred C57BL Disease Models Animal 030104 developmental biology Cancer cell Cancer research lcsh:Q Brain metastasis
Zdroj:	Scientific Reports, Vol 8, Iss 1, Pp 1-13 (2018) Scientific Reports
ISSN:	2045-2322
DOI:	10.1038/s41598-018-26636-6
Popis:	Disruption of the blood-brain barrier (BBB) by cancer cells is linked to metastatic tumor initiation and progression; however, the pathways that drive these events remain poorly understood. Here, we have developed novel patient-derived xenograft (PDX) models of brain metastases that recapitulate pathological growth features found in original patient samples, thus allowing for analysis of BBB disruption by tumor cells. We report that the BBB is selectively disrupted in brain metastases, in part, via inhibition of the endothelial cell-expressed docosahexaenoic acid (DHA) transporter, major facilitator superfamily domain 2a (Mfsd2a). Loss of Mfsd2a expression in the tumor endothelium results in enhanced BBB leakage, but reduced DHA transport and altered lipid metabolism within metastases. Mfsd2a expression in normal cerebral endothelial cells is cooperatively regulated by TGFβ and bFGF signaling pathways, and these pathways are pathologically diminished in the brain metastasis endothelium. These results not only reveal a fundamental pathway underlying BBB disruption by metastatic cancer cells, but also suggest that restoring DHA metabolism in the brain tumor microenvironment may be a novel therapeutic strategy to block metastatic cell growth and survival.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bed6a173595bee6b2be657c1bc1ad064 http://link.springer.com/article/10.1038/s41598-018-26636-6 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.