title: Antiangiogenic and tumour inhibitory effects of downregulating tumour endothelial FABP4.
abstract: 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.
authors: Hypoxia and Growth Factor Group, WIMM, Department of Oncology, University of Oxford, Oxford, UK.
authors: U
authors: U
authors: Harjes
authors: Hypoxia and Growth Factor Group, WIMM, Department of Oncology, University of Oxford, Oxford, UK.
authors: E
authors: E
authors: Bridges
authors: Department of Gynecologic Oncology, University of Texas, Austin, TX, USA.
authors: K M
authors: KM
authors: Gharpure
authors: Department of Cellular Pathology, Oxford University Hospitals and NIHR Biomedical Research Centre Oxford, John Radcliffe Hospital, Oxford, UK.
authors: I
authors: I
authors: Roxanis
authors: Hypoxia and Growth Factor Group, WIMM, Department of Oncology, University of Oxford, Oxford, UK.
authors: H
authors: H
authors: Sheldon
authors: Ovarian Cancer Cell Laboratory, WIMM, Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK.
authors: F
authors: F
authors: Miranda
authors: Department of Gynecologic Oncology, University of Texas, Austin, TX, USA.|Center for RNA Interference and Non-Coding RNA, MD Anderson Cancer Center, Department of Gynecologic Oncology, University of Texas, Austin, TX, USA.
authors: L S
authors: LS
authors: Mangala
authors: Department of Gynecologic Oncology, University of Texas, Austin, TX, USA.
authors: S
authors: S
authors: Pradeep
authors: Center for RNA Interference and Non-Coding RNA, MD Anderson Cancer Center, Department of Gynecologic Oncology, University of Texas, Austin, TX, USA.|Department of Cancer Biology, University of Texas, Austin, TX, USA.
authors: G
authors: G
authors: Lopez-Berestein
authors: Ovarian Cancer Cell Laboratory, WIMM, Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK.
authors: A
authors: A
authors: Ahmed
authors: Department of Nutritional Sciences, University of Surrey, Surrey, UK.
authors: B
authors: B
authors: Fielding
authors: Department of Gynecologic Oncology, University of Texas, Austin, TX, USA.|Center for RNA Interference and Non-Coding RNA, MD Anderson Cancer Center, Department of Gynecologic Oncology, University of Texas, Austin, TX, USA.|Department of Cancer Biology, University of Texas, Austin, TX, USA.
authors: A K
authors: AK
authors: Sood
authors: Hypoxia and Growth Factor Group, WIMM, Department of Oncology, University of Oxford, Oxford, UK.
authors: A L
authors: AL
authors: Harris
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D018284:Cystadenocarcinoma, Serous / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011379:Prognosis; D011446:Prospective Studies; D051881:Receptor, Notch1 / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A