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Antiangiogenic and tumour inhibitory effects of downregulating tumour endothelial FABP4
U Harjes1, E Bridges1, K M Gharpure2
1Hypoxia and Growth Factor Group, WIMM, Department of Oncology, University of Oxford, Oxford, UK.
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.
Insights
Targeting fatty acid binding protein 4 (FABP4) in endothelial cells with siRNA reduces tumor growth and blood vessel formation. This approach shows anti-tumor and anti-angiogenic effects with low toxicity, warranting further investigation.
Area of Science:
- Endothelial cell biology
- Tumor angiogenesis
- Fatty acid metabolism
Background:
- Fatty acid binding protein 4 (FABP4) acts as a fatty acid chaperone and is induced during adipocyte differentiation.
- Endothelial FABP4 is induced by NOTCH1 signaling, which is implicated in resistance to antiangiogenic cancer therapies.
Purpose of the Study:
- To investigate the role of FABP4 in endothelial fatty acid metabolism and tumor angiogenesis.
- To evaluate the therapeutic potential of targeting endothelial FABP4.
Main Methods:
- Transient knockdown of FABP4 in human umbilical vein endothelial cells (in vitro).
- Therapeutic delivery of siRNA targeting mouse FABP4 in vivo using ovarian tumor xenografts.
- Analysis of fatty acid metabolism, reactive oxygen species, angiogenesis, tumor growth, and metastasis.
Main Results:
- FABP4 knockdown in endothelial cells increased fatty acid oxidation, reactive oxygen species, and decreased angiogenesis.
- In vivo, NOTCH1 signaling increased endothelial FABP4 expression, which was reduced by combined NOTCH1 and VEGFA inhibition.
- Therapeutic targeting of endothelial FABP4 via siRNA inhibited tumor angiogenesis, growth, and metastasis with minimal toxicity.
Conclusions:
- Endothelial FABP4 plays a significant role in tumor angiogenesis and growth.
- Therapeutic targeting of endothelial FABP4 using siRNA demonstrates potent anti-angiogenic and anti-tumor effects.
- Targeting endothelial FABP4 is a promising therapeutic strategy for cancer treatment with low toxicity.
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