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.

Caveolin-1 in the regulation of cell metabolism: a cancer perspective

“…Fatty acid synthase (FASN) is a crucial enzyme in fatty acid biosynthesis, and catalyzes the formation of palmitate from acetyl-CoA and malonyl-CoA. Aberrant FASN function is associated with tumourigenesis in various human cancers, making it a potential cancer drug target [73–75]. CAV1 and FASN are coordinately regulated in melanoma and prostate cancers, implying that their concomitant expression may enhance tumourigenesis [76–78].…”

Osteoprotegerin rich tumor microenvironment: implications in breast cancer

“…Reduction in FASN enzyme activity by chemical inhibitors including orlistat, cerulenin and triclosan have been reported to remarkably decrease progression in various cancer cell types [68]. FASN is an attractive therapeutic target as it regulates neoplastic transformation, metastasis as well as angiogenic pathways manipulating tumor vascularity and cell proliferation [69]. It also serves as a potential diagnostic and prognostic biomarker as it is secreted in the blood of patients with breast, prostate, colon and ovarian cancers compared with normal healthy subjects [69].…”

“…FASN is an attractive therapeutic target as it regulates neoplastic transformation, metastasis as well as angiogenic pathways manipulating tumor vascularity and cell proliferation [69]. It also serves as a potential diagnostic and prognostic biomarker as it is secreted in the blood of patients with breast, prostate, colon and ovarian cancers compared with normal healthy subjects [69]. In our recent study we demonstrated that compared to HMEC, SUM149PT and SUM1315MO2 breast cancer cells express increased level of FASN [70].…”

Inhibition of Fatty Acid Synthase Sensitizes Prostate Cancer Cells to Radiotherapy

“…It has been suggested that inhibition of FASN may prevent or inhibit metastasis in colorectal cancer (41) and the FASN inhibitor orlistat was shown to decrease angiogenesis and metastases in experimental models (42,43). We tested the ability of C75 to inhibit migration of prostate cancer cells.…”