Abstract
Abstract Activation of the fibroblast growth factor receptor (FGF/FGFR) system has been reported in a large number of human cancers including human hepatocellular carcinoma (HCC). Furthermore, expression of FGFR2 has been associated with aggressive tumor growth and poor prognosis in this tumor entity. Moreover, HCC is known to be a hypervascularized tumor and activation of the FGF/FGFR system is a crucial event in tumor angiogenesis. Hence, we addressed the issue of targeting the FGFR system in HCC (Huh-7, HepG2) and stromal cells (endothelial cells (EC), vascular smooth muscle cells (VSMC), hepatic stellate cells (HSC)). The FGFR inhibitor BGJ398 (Novartis Oncology, Basel, Switzerland) was used to inhibit FGFR activation. Effects of targeting FGFR on growth of cells were determined by MTT assays. Inhibition of constitutive and growth factor induced cell motility was investigated in modified Boyden Chamber assays. Activation of signaling pathways upon treatment with BGJ398 was assessed by Western Blot analyses whereas effects on mediators of tumor angiogenesis (VEGF-A, PDGF-B) where measured by RT-PCR and ELISA, respectively. Results show that inhibition of the FGF/FGFR system with BGJ398 led to dose-dependent inhibition of growth in tumor cells and ECs whereas only minor effects were observed on VSMC and HSCs. Moreover, motility of tumor and stromal cells (ECs, VSMCs, HSCs) was significantly impaired upon constitutive conditions (P<0.05 for all). In addition, FGFR inhibition led to decrease in HSC motility even when cell were incubated with conditioned media from cancer cells (P<0.05). With regards to activation of signaling intermediates, FGFR inhibition impaired constitutive and growth factor induced phosphorylation of Akt and ERK in HCC cell lines, ECs and HSCs whereas only minor effect was observed in VSMCs. Moreover, treatment with BGJ398 led to inhibition of c-Myc expression and significantly reduced VEGF-A production from cancer cells, as determined by Western blotting and ELISA, respectively. Evaluation of effectiveness of BGJ398 in animal models is currently ongoing. However, results so far indicate that targeting FGFR impairs angiogenic signaling and motility in HCC cell lines and stromal cells. Therefore, inhibition of FGFR warrants further evaluation and might be an interesting novel approach for anti-neoplastic treatment protocols in human HCC. 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 4373. doi:1538-7445.AM2012-4373
Published Version
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