Abstract 375: Role of intracrine vascular endothelial growth factor (VEGF) signaling in colorectal cancer cell survival and metastasis.

Abstract

Abstract Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis and vascular function, and it's role in biology are thought to be well understood. Although the effects of VEGF on angiogenesis, i.e. on endothelial cells, have been extensively studied, its effects on tumor cell function remain to be clearly elucidated. Our laboratory has demonstrated the VEGF receptors are present and active on colorectal cancer (CRC) cells. Recently we have studied the phenotypic changes in human CRC cells to determine the role of autocrine/intracrine VEGF signaling on tumor cell function. Using cell lines with somatic knockout of the VEGF gene we have been able to show that loss of VEGF expression led to significantly decreased cell growth and increased spontaneous apoptosis in CRC cells. Depletion of VEGF also increased the in vitro sensitivity of cells to the cytotoxic effects of the chemotherapeutic agent 5-fluorouracil. Importantly, these effects are not mediated in an autocrine or paracrine fashion, as neutralization of extracellular VEGF with a monoclonal antibody, or inhibition of kinase activity with small molecule inhibitors had no effect on CRC cell survival. These studies support a novel role for VEGF in cell survival as an intracrine factor. In our attempt to characterize the molecular mechanisms responsible for the intracrine pro-survival role of VEGF, we have performed gene microarray analyses on a pair of CRC cells with and without expression of VEGF. These studies show a clear difference in expression patterns of genes between cells that produce or lack VEGF, but surprisingly find no significant changes in gene expression when VEGF function is inhibited by functional antibodies (Bevacizumab). Our preliminary analyses of the gene expression profiles indicate that CRC cells lacking VEGF have increased levels of multiple receptor tyrosine kinases. In other biochemical assays, we also find that cells lacking VEGF have increased activation of survival and proliferation pathways compared to normal cells. Based on our data, we hypothesize that loss of VEGF may induce activation of other survival pathways that compensate for depletion of VEGF. Our microarray studies also indicate significant increases in a factor that has been implicated in increased metastasis in breast and lung cancer. This factor may be responsible for the increased migration and invasion of CRC cells lacking VEGF observed in vitro. Future studies will elucidate the exact role of VEGF in tumor cell survival and metastasis. Citation Format: Rajat Bhattacharya, Shaija Samuel, Fan Fan, Ganiraju Manyam, Veera Baladandayuthapani, Lee Ellis. Role of intracrine vascular endothelial growth factor (VEGF) signaling in colorectal cancer cell survival and metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 375. doi:10.1158/1538-7445.AM2013-375