MHCC97-L and MHCC97-H cells demonstrate a mesenchymal phenotype with decreased expression of E-cadherin and increased expression of c-Met, fibronectin, and Zeb2 compared with Huh7 and Hep3B cells, which have an epithelial phenotype. PHA665752 treatment blocked phosphorylation of c-Met and downstream phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase/Erk pathways, inhibited cell proliferation, and induced apoptosis in

c-Met–positive MHCC97-L and MHCC97-H cells. In xenograft models, administration of PHA665752 significantly inhibited c-Met–positive MHCC97-L and MHCC97-H tumor growth, and PHA665752-treated tumors U0126 demonstrated marked reduction of both c-Met phosphorylation and cell proliferation. c-Met–negative Huh7 and Hep3B cells were not affected by c-Met inhibitor treatment in vitro or in vivo. In addition, c-Met–positive MHCC97-L and MHCC97-H cells demonstrated cancer stem cell–like characteristics, such as resistance

to chemotherapy, tumor sphere formation, and increased expression of CD44 and ABCG2, and PHA665752 treatment suppressed tumor sphere formation and inhibited CD44 expression. Conclusion: c-Met represents a potential target of personalized treatment for HCC with an active HGF/c-Met pathway. (HEPATOLOGY 2011;) Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related death worldwide and is the only carcinoma Pembrolizumab with increasing mortality in the United States during the last decade.1 Although surgical resection and transplantation have significantly improved MK-8669 survival in patients with small tumors and no evidence of invasion or metastasis, the prognosis of HCC for late stage diseases remains very poor.2 In addition, recurrent and metastatic disease remain the most important factors for survival in HCC transplantation patients.3 In addition to tumor number, size, and vascular invasion observed on imaging studies, c-Met expression is a molecular characteristic that appears to

predict poor survival in HCC (Supporting Table 1).4-7 Hepatocyte growth factor (HGF) is an autocrine and paracrine factor that is produced by stromal cells. HGF acts on c-Met, a high-affinity tyrosine kinase receptor.8 During development, homozygous deletion of HGF or c-Met is embryonic-lethal.9, 10 Although HGF/c-Met signaling does not play a role in liver homeostasis during normal physiologic conditions, many studies have demonstrated the important role of HGF in liver regeneration, hepatocyte survival, and tissue remodeling after acute injury.11, 12 After c-Met phosphorylation and activation, multiple signaling pathways are involved as downstream targets, such as the phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/Erk pathways.