In hepatocellular carcinoma (HCC), the progression of malignant hepatocytes frequently depends on transforming growth factor (TGF)-beta provided by stromal cells. TGF-beta induces an epithelial to mesenchymal transition (EMT) of oncogenic Ras-transformed hepatocytes and an upregulation of platelet-derived growth factor (PDGF) signaling. To analyze the influence of the hepatic tumor-stroma crosstalk onto tumor growth and progression, we co-injected malignant hepatocytes and myofibroblasts. For this, we either used in vitro activated p19ARF myofibroblasts or in vivo activated
myofibroblasts derived from physiologically inflamed livers of Mdr2/p19ARF double null mice. We demonstrate that co-transplantation of myofibroblasts VX-689 supplier with Ras-transformed hepatocytes strongly enhances tumor growth. Genetic interference with the PDGF signaling decreases tumor cell growth and maintains plasma membrane-located E-cadherin and beta-catenin at the tumor-host border, indicating a blockade of hepatocellular
EMT. We further generated a collagen gel-based three dimensional HCC model in vitro to monitor the myofibroblast-induced invasion of micro-organoid HCC spheroids. This invasion was diminished after inhibition of TGF-beta or PDGF signaling. These data suggest that the TGF-beta/PDGF axis is crucial during hepatic tumor-stroma crosstalk, regulating both tumor growth and cancer progression. Poster No. 139 The Role of PI3K/Akt Signaling and MMP(s) in Shh/Gli-mediated EMT and Metastatic Potential NVP-AUY922 in vitro of Gastric Cancer Young A. Yoo 1 , Myoung Hee Kang 2, Han Na Kang 2, Jung Lim Kim2, Jun Suk Kim 3, Sang Cheul Oh3 1 Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, enough Seoul, Korea Republic, 2 Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul, Korea Republic, 3 Division of Oncology/Hematology, Department of Internal Medicine,
Korea University College of Medicine, Korea University, Seoul, Korea Republic The activation of Sonic hedgehog (Shh) signaling is involved in the progression and invasion of various tumors, including gastric carcinoma. Epithelial-mesenchymal transition (EMT) and matrix metalloproteinases (MMPs) have been implicated in facilitating the invasion and metastatsis. Herein, we investigated the impact of phosphoinositide 3-kinase (PI3K)/Akt pathway and MMPs activity on the Shh/Gli-mediated EMT and invasion of gastric cancer cells. We found that TSA HDAC stimulation of N-Shh in gastric cancer cells enhanced cellular motility and invasiveness and induced a full EMT process characterized by Snail induction and E-cadherin down-regulation.