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Fatty acid binding protein 4 (FABP4) is a fatty acid chaperone, which is induced during adipocyte differentiation. Previously we have shown that FABP4 in endothelial cells is induced by the NOTCH1 signalling pathway, the latter of which is involved in mechanisms of resistance to antiangiogenic tumour therapy. 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 mouse FABP4, we investigated the effect of endothelial 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 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 endothelial FABP4. Therapeutic targeting of endothelial FABP4 by siRNA in vivo has antiangiogenic and antitumour effects with minimal toxicity and should be investigated further.

Original publication

DOI

10.1038/onc.2016.256

Type

Journal article

Journal

Oncogene

Publication Date

16/02/2017

Volume

36

Pages

912 - 921

Keywords

Angiogenesis Inhibitors, Animals, Apoptosis, Biomarkers, Tumor, Cell Movement, Cell Proliferation, Cystadenocarcinoma, Serous, Fatty Acid-Binding Proteins, Female, Follow-Up Studies, Human Umbilical Vein Endothelial Cells, Humans, Mice, Mice, Nude, Neoplasm Grading, Neoplasm Invasiveness, Neovascularization, Pathologic, Ovarian Neoplasms, Prognosis, Prospective Studies, Receptor, Notch1, Signal Transduction, Survival Rate, Tumor Cells, Cultured, Vascular Endothelial Growth Factor A, Xenograft Model Antitumor Assays