Under normal physiological conditions, the hepatocyte growth factor (HGF) and its receptor, the MET transmembrane tyrosine kinase (cMET), are involved in embryogenesis, morphogenesis, and wound healing. The HGF-cMET axis promotes cell survival, proliferation, migration, and invasion via modulation of epithelial-mesenchymal interactions. Hepatocellular cancer (HCC) is the third most common cause of worldwide cancer-related mortality; advanced disease is associated with a paucity of therapeutic options and a five-year survival rate of only 10%. Dysregulation of the HGF-cMET pathway is implicated in HCC carcinogenesis and progression through activation of multiple signaling pathways; therefore, cMET inhibition is a promising therapeutic strategy for HCC treatment. The authors review HGF-cMET structure and function in normal tissue and in HCC, cMET inhibition in HCC, and future strategies for biomarker identification. 1. Introduction Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the third most common cause of global cancer related mortality [1, 2]. HCC burden disproportionately impacts developing countries and males; as of 2008, 85% of cases occurred in Africa and Asia, with worldwide male: female sex ratio of 2.4 [2]. Risk factors for the development of HCC include chronic liver inflammation from hepatitis B and C infection, autoimmune hepatitis, excessive alcohol use, nonalcoholic steatohepatitis, primary biliary cirrhosis, environmental carcinogens such as aflatoxin B, and genetic metabolic disease (such as hemochromatosis and alpha-1 antitrypsin deficiency). Prognostic and therapeutic options are dependent upon the severity of underlying liver disease, and median overall survival (OS) for metastatic or locally advanced disease is estimated at 5–8 months. HCC is relatively refractory to cytotoxic chemotherapy, likely due to overexpression of multidrug-resistant genes [3], protein products such as heat shock 70 [4] and P-glycoprotein [5], and p53 mutations. Presently, systemic therapeutic options in the locally advanced or metastatic setting are limited to sorafenib, an oral multikinase inhibitor targeting Raf kinase, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptor tyrosine kinase signaling. Although the transition from normal hepatocyte to HCC is not fully understood, hepatocarcinogenesis is a complex multistep process driven by accumulation of heterogeneous molecular alterations from initial hepatocyte injury to metastatic invasion. Inflammation results in hepatocyte
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