8, 16 Within cancer, HGF/c-Met mediates a proliferative advantage and promotes tumor invasion and metastasis.8, 16-19 As a result of the strong clinical correlation between c-Met expression and metastatic disease, c-Met is considered a therapeutic target against tumor growth and metastasis in lymphoma, gastric cancer, melanoma, and lung cancers. Within select cancers, mutations often result in c-Met activation.20-22 Although multiple studies

have demonstrated that c-Met overexpression is linked to poor prognosis in HCC,4-7 the evidence that c-Met inhibition is a viable treatment for HCC has not been established. One feature that links c-Met activation to cancer metastasis is epithelial-to-mesenchymal transition (EMT). EMT is a transdifferentiation program by which epithelial cells lose cell–cell

contact and acquire mesenchymal characteristics, including motility and invasion.23 selleckchem One of the hallmarks of EMT is loss of E-cadherin–mediated tight junctions through increased expression of E-box repressors such as Zeb1, Zeb2, Snail, and Twist. The EMT program is activated by multiple extracellular signals, including HGF, and we recently demonstrated that HGF treatment was capable of inducing and sustaining a mesenchymal phenotype within murine models of liver cancer.24 Here we demonstrate that the c-Met–positive human HCC cell lines MHCC97-L and MHCC97-H25 display a mesenchymal

C646 mw phenotype and cancer stem cell (CSC)-like characteristics, compared with c-Met negative Huh7 and Hep3B cells, which have an epithelial phenotype. PHA665752, a selective inhibitor of c-Met,26, 27 suppresses cell proliferation and induces apoptosis in c-Met–positive MHCC97-L and MHCC97-H cells, and has no effect on Huh7 and Hep3B cells. Using a xenograft model, we demonstrate that c-Met inhibition is capable of significantly inhibiting the growth of c-Met–positive HCC tumors. BrdU, 5-bromo-2′-deoxyuridine; CSC, cancer stem cell; EMT, see more epithelial-mesenchymal transition; FITC, fluorescein isothiocyanate; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; MAPK, mitogen-activated protein kinase; MEK1, mitogen-activated protein kinase kinase 1; PI3K, phosphoinositide 3-kinase. See Supporting Materials and Methods. The human HCC cell line Huh7 was provided by Jianming Hu, Penn State College of Medicine, and cultured as described.28 The human HCC cell line Hep3B was provided by Xin Chen, Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, and maintained as described.29 The human HCC cell lines MHCC97-L and MHCC97-H were provided by Xinwei Wang, National Cancer Institute, under agreement with the Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.