Cancer cell-associated fatty acid synthase activates endothelial cells and promotes angiogenesis in colorectal cancer
| Autor: | Ji Tae Kim, Victoria A. Elliott, Joseph Valentino, Piotr Rychahou, Janna M. Neltner, Yekaterina Y. Zaytseva, W. Conan Mustain, Eun Y. Lee, Kathleen L. O'Connor, Heidi L. Weiss, Tianyan Gao, B. Mark Evers |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Cancer Research Angiogenesis Original Manuscript Chick Embryo Metastasis Neovascularization chemistry.chemical_compound Downregulation and upregulation Cell Line Tumor medicine Animals Humans Neovascularization Pathologic biology Endothelial Cells General Medicine medicine.disease Vascular Endothelial Growth Factor Receptor-2 digestive system diseases Vascular endothelial growth factor Disease Models Animal Fatty acid synthase Vascular endothelial growth factor A Gene Expression Regulation Matrix Metalloproteinase 9 chemistry Gene Knockdown Techniques Cancer cell biology.protein Cancer research Heterografts Fatty Acid Synthases medicine.symptom Colorectal Neoplasms Signal Transduction |
| Zdroj: | Carcinogenesis. 35:1341-1351 |
| ISSN: | 1460-2180 0143-3334 |
| DOI: | 10.1093/carcin/bgu042 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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