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Antiangiogenic and tumour inhibitory effects of downregulating tumour endothelial FABP4

Harjes, U, Bridges, E, Gharpure, KM, Roxanis, I, Sheldon, H, Miranda, F, Mangala, LS, Pradeep, S, Lopez-Berestein, G, Fielding, BA, Ahmed, A, Sood, AK and Harris, A (2016) Antiangiogenic and tumour inhibitory effects of downregulating tumour endothelial FABP4 Oncogene.

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Abstract

Fatty acid binding protein 4 (FABP4) is a fatty acid chaperone, which is induced during adipocyte differentiation. Previously we have shown that endothelial FABP4 is induced by the NOTCH1 signalling pathway, which is involved in mechanisms of resistance to anti-angiogenic tumour therapy1. Here, we investigated the role of FABP4 in endothelial fatty acid metabolism and tumour angiogenesis. We analysed the effect of transient FABP4 knockdown in human umbilical vein endothelial cells on fatty acid metabolism, viability, and angiogenesis. Through therapeutic delivery of siRNA targeting murine FABP4, we investigated the effect of stromal FABP4 knockdown on tumour growth and blood vessel formation. In vitro, siRNA-mediated FABP4 knockdown in endothelial cells led to a marked increase of endothelial fatty acid oxidation, an increase of reactive oxygen species (ROS), and decreased angiogenesis. In vivo, we found that increased NOTCH1 signalling in tumour xenografts led to increased expression of endothelial FABP4 that decreased when NOTCH1 and VEGFA inhibitors were used in combination. Angiogenesis, growth, and metastasis in ovarian tumour xenografts were markedly inhibited by therapeutic siRNA delivery targeting mouse FABP4. Therapeutic targeting of endothelial FABP4 by siRNA in vivo has anti-angiogenic and anti-tumour effects with minimal toxicity and should be investigated further.

Item Type: Article
Subjects : Biosciences
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
AuthorsEmailORCID
Harjes, UUNSPECIFIEDUNSPECIFIED
Bridges, EUNSPECIFIEDUNSPECIFIED
Gharpure, KMUNSPECIFIEDUNSPECIFIED
Roxanis, IUNSPECIFIEDUNSPECIFIED
Sheldon, HUNSPECIFIEDUNSPECIFIED
Miranda, FUNSPECIFIEDUNSPECIFIED
Mangala, LSUNSPECIFIEDUNSPECIFIED
Pradeep, SUNSPECIFIEDUNSPECIFIED
Lopez-Berestein, GUNSPECIFIEDUNSPECIFIED
Fielding, BAUNSPECIFIEDUNSPECIFIED
Ahmed, AUNSPECIFIEDUNSPECIFIED
Sood, AKUNSPECIFIEDUNSPECIFIED
Harris, AUNSPECIFIEDUNSPECIFIED
Date : 29 August 2016
Identification Number : 10.1038/onc.2016.256
Copyright Disclaimer : This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Depositing User : Symplectic Elements
Date Deposited : 16 Jun 2016 10:15
Last Modified : 06 Dec 2016 15:52
URI: http://epubs.surrey.ac.uk/id/eprint/811013

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