Based on our data that c-Met–negative HCC cells do not respond to c-Met inhibition, we propose that c-Met inhibition may show a blunted survival benefit within all HCC patients. We propose that c-Met inhibitor trials

would perhaps show an improved benefit for c-Met–positive HCC, a personalized approach that requires patients to be stratified based on c-Met expression prior to treatment. This type of personalized treatment has been used in the field of breast cancer for over a decade in the treatment of HER-2–positive disease with HER-2 inhibitors.37, 38 One potential factor driving poor prognosis is that c-Met activation JAK inhibitor is linked to invasion and metastasis.39 Although the exact mechanisms that initiate invasion and metastasis in HCC are unknown and likely multifactorial, a transition to a mesenchymal phenotype has been proposed by Thiery31 and Bernards and Weinberg32 to be a critical step. Using a murine

liver cancer model, we demonstrated recently that an activated HGF/c-Met pathway drives a mesenchymal phenotype, with aggressive and invasive growth.24 Establishing a Caspase inhibitor metastatic lesion is a complex, multistep process. One central finding in metastatic carcinoma is loss of E-cadherin.23, 40 E-cadherin is an important cell–cell adhesion molecule, and inhibition of E-cadherin transcription is a critical part of maintaining a mesenchymal phenotype with the capability of invasion. E-cadherin transcriptional repression is associated

with poor prognosis and metastatic disease in a variety of carcinomas, including advanced HCC.33 Other factors that likely contribute to metastatic HCC include activation of broader EMT programs by the E-box repressors Zeb1/Zeb2, Twist, and Snail and increased matrix metalloproteinase expression. Understanding the specific mechanisms by which EMT initiators and downstream pathways signal through E-cadherin transcriptional repressors will be important in terms of designing targeted therapy for metastatic disease. At present, the specific role of c-Met inhibition in targeting metastatic disease has not been established. Upon ligand binding, c-Met undergoes autophosphorylation of specific tyrosine residues within the intracellular domain. Tyrosine phosphorylation Montelukast Sodium is critical for the activation of the intrinsic kinase of c-Met, which propagates multiple downstream signaling pathways such as PI3K/Akt and MAPK/Erk.8, 13-15 c-Met phosphorylation-induced activation of the PI3K/Akt and MAPK/Erk pathways controls cell proliferation, resistance to apoptosis, and cytoskeletal rearrangement. c-Met inhibition is able to suppress both PI3K/Akt and MAPK/Erk pathways in c-Met–positive HCC cells in vitro, and c-Met inhibition appears to be more effective at reducing cancer cell proliferation compared with combination treatment with PI3K and MEK1 inhibitors.