Abstract 1203: Targeting FGFR4 in colorectal cancer cells

Abstract

Abstract Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in the regulation of cell proliferation, differentiation and survival as well as tumor development and therefore constitute prominent targets for cancer therapy. Over-expression of FGFR4 has been described in various cancer types and was also related to tumor aggressiveness. Reports concerning the role of FGFR4 in colorectal cancer (CRC) are still under dispute. In our study we found FGFR4 expression to be significantly up-regulated in human CRC tissue compared to normal mucosa. CRC cell line models over-expressing FGFR4 were created by transfecting SW480, HCT116 and HT29 colon carcinoma cells with a FGFR4 expression vector. This resulted in an increase of cell proliferation and colony formation under standard tissue culture conditions and colony outgrowth in soft agar was stimulated. In xenografted SCID mice tumor growth was significantly increased by FGFR4 over-expression. siRNA mediated knock down of FGFR4 in the high FGFR4 expressing cell lines HCT116 and HT29 resulted in decreased cell proliferation, viability and colony outgrowth in 2-dimensional growth assays. Additionally a dominant negative FGFR4 adenoviral construct inhibited 3-dimensional anchorage independent growth and suppressed tumor growth in vivo almost completely. Ongoing experiments analyze the effects of a soluble FGFR4 variant on 2-dimensional and 3-dimensional growth. FGFR4 up-regulation resulted in activation of survival pathways via FRS2 and PI3K leading to phosphorylation of GSK3β and S6. Signaling effects by blockage of FGFR4 dependent signaling via siRNA and the dominant negative adenoviral construct are currently being investigated. Based on our results we identified the FGFR4 as an important oncogene in the carcinogenesis which is involved in the tumor growth regulation of CRC in vitro and in vivo. Consequently FGFR4 should be regarded as a new therapeutic target in CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1203. doi:1538-7445.AM2012-1203