However, despite profound therapeutic implications the prognostic relevance of CSCs and their cellular localization R788 mw within the tumor formation remain controversial. Methods: Expression levels and localization of established CSC markers were assessed in 30 HCCs using qRT-PCR, imunohistochemistry and Western-Blotting. Whole

transcriptome analyses of different tumor regions as well as tumor-surrounding liver (SL) were performed to identify associated signaling pathways and integrated with our existing HCC database. Results: Expression patterns of established CSC markers were surprisingly heterogeneous. Activation of CSCs was predominantly observed in SL and continuously decreased to the tumor core. Consistently, tran-scriptome profiles between SL and different tumor regions were quite distinct. A generated gene expression-signature showed activation of pathways related to proliferation as well as apop-tosis in the tumor tissue, while the invasive tumor margin (TM) was characterized by inflammatory and EMT-related gene sets as well as activation of pro-survival signaling such as ERK and FOS. Consistently, integration of the different signatures with our database of AZD0530 molecular weight 53 HCC revealed that the TM signature was associated with the survival of

HCC patients. Conclusion: CSCs in HCC are heterogeneous. The CSC phenotype is predominantly determined by the permissive tumor microenvironment. However, pro-oncogenic properties might originate in the TM. The activation of key oncogenic features as well as immune-response signaling indicates that

the cross-talk between tumor and microenvironment might be a promising therapeutic and/ or preventive target. Disclosures: Marcus A. Woerns – Advisory Committees or Review Panels: Bayer, Bayer Peter R. Galle – Advisory Committees or Review medchemexpress Panels: Bayer, BMS, Lilly, Daiichi, Jennerex; Consulting: Medimmune; Grant/Research Support: Roche, Lilly; Speaking and Teaching: Bayer, BMS The following people have nothing to disclose: Michael Fischer, Stefan Heinrich, Jesper B. Andersen, Martin F. Sprinzl, Ines Gockel, Snorri S. Thorgeirsson, Hauke Lang, Jens U. Marquardt BACKGROUND & AIMS: Oral supplementation with branched-chain amino acids (BCAA; leucine, isoleucine, and valine) in patients with liver cirrhosis potentially suppresses incidence of hepatocellular carcinoma and improves event-free survival. However, the detailed mechanisms by which BCAA act on hepatic fibrosis have not been fully elucidated. METHODS: BCAA were administered to atherogenic and high-fat (Ath & HF) diet-induced nonalcoholic steatohepatitis (NASH) model mice and platelet-derived growth factor C transgenic mice (Pdgf-c Tg). Liver histology, tumor incidence, and gene expression profiles were evaluated. RESULTS: Ath & HF diet mice developed hepatic tumors at a high frequency at 68 weeks.