Tumor-Specific Expression Of Fatty Acid Synthase Promotes Angiogenesis In Colorectal Cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Up regulation 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 of metastasis by FASN are elusive. The induction of angiogenesis is crucial for metastasis. Therefore, the purpose of the present study was (i) to determine the role of FASN in regulation of secretion of angiogenic factors by CRC cells, (ii) to evaluate the effect of tumor-specific expression of FASN on endothelial cells, and (iii) to assess the role of FASN in regulation of tumor vasculature. METHODS: The effect of FASN inhibition on secretion of angiogenic factors was analyzed using the Human Angiogenesis Antibody Array 1 (RayBiotech). Co-culture of CRC and HMVEC-L cells was used to assess the effect of FASN expression on growth, migration, and tube formation of endothelial cells. To evaluate the effect of FASN on vasculature, we utilized murine colonoscopy, the orthotopic colon cancer model, the chick chorioallantoic membrane (CAM) model, and the Matrigel plug assay. RESULTS: We found that inhibition of FASN is associated with an evident change in the profile of secreted angiogenic factors by CRC cells and this change is associated with a significant decrease in microvessel density as determined by analysis of CD31 staining (Aperio Image Scope) in orthotopic colon tumors. A decrease in expression of FASN is also associated with “normalization” of tumor vasculature in the CAM model. The mechanisms of inhibition of angiogenesis by knockdown of FASN included down regulation of VEGF189, an isoform associated with aggressive CRC, up regulation of anti-angiogenic isoform VEGF165b, and a decrease in expression and activity of MMP-9. Furthermore, medium conditioned on FASN-knockdown CRC cells inhibited proliferation, migration, and tube formation of endothelial cells via inhibition of VEGFR-2 activation and its downstream signaling as compared to control medium. CONCLUSIONS: This study suggests that FASN promotes angiogenesis via alteration of the profile of secreted angiogenic factors by CRC cell and stimulation of endothelial cell proliferation. Furthermore, the regulation of angiogenesis by FASN, at least in part, is mediated by up-regulation of VEGF189, a VEGF-A isoform that tightly correlates with poor prognosis in CRC, and by an increase in activity of MMP-9. Together, these findings suggest that inhibition of FASN upstream of VEGF-A and other angiogenic pathways can be a novel therapeutic strategy to prevent or inhibit metastasis in CRC. Citation Format: Yekaterina Y. Zaytseva, Victoria Elliott, Piotr Rychahou, William Mustain, Ji Tae Kim, Joseph Valentino, Tianyan Gao, Kathleen O'Connor, Janna Neltner, Heidi Weiss, B. Mark Evers. Tumor-specific expression of fatty acid synthase promotes angiogenesis in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1009. doi:10.1158/1538-7445.AM2014-1009