title: Cancer cell-associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer.
abstract: 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.
authors: Markey Cancer Center.
authors: Yekaterina Y
authors: YY
authors: Zaytseva
authors: Markey Cancer Center.
authors: Victoria A
authors: VA
authors: Elliott
authors: Markey Cancer Center, Department of Surgery.
authors: Piotr
authors: P
authors: Rychahou
authors: Department of Surgery.
authors: W Conan
authors: WC
authors: Mustain
authors: Markey Cancer Center, Department of Surgery.
authors: Ji Tae
authors: JT
authors: Kim
authors: Department of Surgery.
authors: Joseph
authors: J
authors: Valentino
authors: Department of Molecular and Cellular Biochemistry.
authors: Tianyan
authors: T
authors: Gao
authors: Markey Cancer Center.
authors: Kathleen L
authors: KL
authors: O'Connor
authors: Department of Pathology and Laboratory Medicine and.
authors: Janna M
authors: JM
authors: Neltner
authors: Markey Cancer Center, Department of Surgery, Department of Pathology and Laboratory Medicine and.
authors: Eun Y
authors: EY
authors: Lee
authors: Markey Cancer Center, Department of Biostatistics, University of Kentucky, Lexington, KY 40536, USA.
authors: Heidi L
authors: HL
authors: Weiss
authors: Markey Cancer Center, Department of Surgery, mark.evers@uky.edu.
authors: B Mark
authors: BM
authors: Evers
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002642:Chick Embryo; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D064429:Fatty Acid Synthases; D040301:Vascular Endothelial Growth Factor Receptor-2; D020780:Matrix Metalloproteinase 9