Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C1658953 (
tumor vasculature
)
2,390
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Cancer cell-associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer. 2451 Feb 38
