RESUMO
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.
Assuntos
Inibidores da Angiogênese/metabolismo , Cistadenocarcinoma Seroso/prevenção & controle , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Neovascularização Patológica/prevenção & controle , Neoplasias Ovarianas/prevenção & controle , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Movimento Celular , Proliferação de Células , Cistadenocarcinoma Seroso/irrigação sanguínea , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Seguimentos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Camundongos , Camundongos Nus , Gradação de Tumores , Invasividade Neoplásica , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neoplasias Ovarianas/irrigação sanguínea , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico , Estudos Prospectivos , Receptor Notch1/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tumour tissue is characterised by fluctuating oxygen concentrations, decreased nutrient supply, and acidic pH. The primarily glycolytic metabolism of tumour cells contributes to this, with increased glucose consumption and increased lactate secretion. Endothelial cells are particularly challenged when recruited towards the tumour metabolic environment. They are required to proliferate and form functional networks in order to establish continuous blood flow. Considering that deregulated metabolism is an emerging hallmark of cancer and target of tumour therapy, it is of importance to incorporate the current knowledge about how the tumour metabolic environment, as a therapy target, can affect endothelial cell metabolism and the angiogenic response. Recent studies have shown differences in metabolic pathways in endothelial cells compared with other normal or tumour tissues. Therefore, we have reviewed relevant literature on endothelial metabolism and the response to angiogenic activation in conditions of metabolic stress.