Cancer cell-associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer.

Autor:	Zaytseva YY; Markey Cancer Center., Elliott VA; Markey Cancer Center., Rychahou P; Markey Cancer Center, Department of Surgery., Mustain WC; Department of Surgery., Kim JT; Markey Cancer Center, Department of Surgery., Valentino J; Department of Surgery., Gao T; Department of Molecular and Cellular Biochemistry., O'Connor KL; Markey Cancer Center., Neltner JM; Department of Pathology and Laboratory Medicine and., Lee EY; Markey Cancer Center, Department of Surgery, Department of Pathology and Laboratory Medicine and., Weiss HL; Markey Cancer Center, Department of Biostatistics, University of Kentucky, Lexington, KY 40536, USA., Evers BM; Markey Cancer Center, Department of Surgery, mark.evers@uky.edu.
Jazyk:	angličtina
Zdroj:	Carcinogenesis [Carcinogenesis] 2014 Jun; Vol. 35 (6), pp. 1341-51. Date of Electronic Publication: 2014 Feb 07.
DOI:	10.1093/carcin/bgu042
Abstrakt:	Upregulation of fatty acid synthase (FASN), a key enzyme of de novo lipogenesis, is associated with metastasis in colorectal cancer (CRC). However, the mechanisms of regulation are unknown. Since angiogenesis is crucial for metastasis, we investigated the role of FASN in the neovascularization of CRC. The effect of FASN on tumor vasculature was studied in orthotopic CRCs, the chick embryo chorioallantoic membrane (CAM) and Matrigel plug models using immunohistochemistry, immunofluorescent staining and confocal microscopy. Cell secretion was evaluated by ELISA and antibody arrays. Proliferation, migration and tubulogenesis of endothelial cells (ECs) were assessed in CRC-EC coculture models. In this study, we found that stable knockdown of FASN decreased microvessel density in HT29 and HCT116 orthotopic CRCs and resulted in 'normalization' of tumor vasculature in both orthotopic and CAM models. Furthermore, FASN regulated secretion of pro- and antiangiogenic factors, including vascular endothelial growth factor-A (VEGF-A). Mechanisms associated with the antiangiogenic activity noted with knockdown of FASN included: downregulation of VEGF(189), upregulation of antiangiogenic isoform VEGF(165b) and a decrease in expression and activity of matrix metalloproteinase-9. Furthermore, conditioned medium from FASN knockdown CRC cells inhibited activation of vascular endothelial growth factor receptor-2 and its downstream signaling and decreased proliferation, migration and tubulogenesis of ECs as compared with control medium. Together, these results suggest that cancer cell-associated FASN regulates tumor vasculature through alteration of the profile of secreted angiogenic factors and regulation of their bioavailability. Inhibition of FASN upstream of VEGF-A and other angiogenic pathways can be a novel therapeutic strategy to prevent or inhibit metastasis in CRC. (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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