According to the International Agency for Research on Cancer, approximately 670,000 new cases of hepatocellular carcinoma (HCC) developed in 2005, making it the fifth most common cancer and third most common cause of cancer-related death worldwide. HCC is a complex and heterogeneous tumor with several genomic alterations. There is evidence of aberrant activation of several signaling cascades such as EGFR, Ras/Raf/MEK, PI3K/mTOR, HGF/MET, Wnt, Hedgehog and apoptotic signaling pathway. Recently a multikinase inhibitor, sorafenib, has shown survival benefits in patients with advanced HCC. It has been proposed that signaling pathway disruption in cancer can be grouped in six function capabilities, some of which need to be altered for cancer development: self-sufficiency in growth signals, insensitivity to anti-growth signals, evading apoptosis, limitless replicative potential, sustained angiogenesis and tumor invasion and metastases. The aim is to integrate these concepts into the molecular pathogenesis of HCC. It has also been proposed that there are common disturbances universal to all liver cancers on top of the more specific mechanisms. Based on this basic research, a molecular targeted agent has recently been developed. There have been no effective chemotherapeutic agents for advanced HCC. Sorafenib, an oral multikinase inhibitor, has set a milestone in the management of HCC in that it is the first agent to significantly improve the overall survival in patients with advanced HCC in a double-blind, placebo-controlled, phase III study. Clinical trials testing new agents for first- and second-line agents, as well as in combination with existing treatment options such as transarterial chemoembolization or arterial infusion chemotherapy, are ongoing. The results of these trials are therefore eagerly awaited.

Kim JH, Yu SJ, Park BL, Cheong HS, Pasaje CFA, Bae JS, Lee HS, Shin HD, Kim YJ: TGFBR3 polymorphisms and its haplotypes associated with chronic hepatitis B virus infection and age of hepatocellular carcinoma occurrence. Dig Dis 2011;29:278–283.
Yamazaki K, Masugi Y, Sakamoto M: Molecular pathogensis of hepatocellular carcinoma: altering transforming growth factor-β signaling in hepatocarcinogenesis. Dig Dis 2011;29:284–288.
Farazi PA, DePinho RA: Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 2006;6:674–687.
Minguez B, Tovar V, Chiang D, Villanueva A, Llovet JM: Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol 2009;25:186–194.
Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM: Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 2007;27:55–76.
Laurent-Puig P, Zucman-Rossi J: Genetics of hepatocellular tumors. Oncogene 2006;25:3778–3786.
Llovet JM, Bruix J: Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008;48:1312–1327.
Murata K, Suzuki H, Okano H, Oyamada T, Yasuda Y, Sakamoto A: Hypoxia-induced des-γ-carboxyprothrombin production in hepatocellular carcinoma. Int J Oncol 2010;36:161–170.
Murata K, Suzuki H, Okano H, Oyamada T, Yasuda Y, Sakamoto A: Cytoskeletal changes during epithelial-to-fibroblastoid conversion as a crucial mechanism of des-γ-carboxyprothrombin production in hepatocellular carcinoma. Int J Oncol 2009;35:1005–1014.
Murata K, Sakamoto A: Impairment of clathrin-mediated endocytosis via cytoskeletal change by epithelial to fibroblastoid conversion in HepG2 cells: a possible mechanism of des-γ-carboxyprothrombin production in hepatocellular carcinoma. Int J Oncol 2008;33:1149–1155.
Ueshima K, Kudo M, Takita M, Nagai T, Tatsumi C, Ueda T, Kitai S, Ishikawa E, Yada N, Inoue T, Hagiwara S, Minami Y, Chung H, Sakurai T: Des-gamma-carboxyprothrombin may be a promising biomarker to determine the therapeutic efficacy of sorafenib for hepatocellular carcinoma. Dig Dis 2011;29: 321–325.
Kondrup J, Muller MJ: Energy and protein requirements of patients with chronic liver disease. J Hepatol 1997;27:239–247.
Moriwaki H, Miwa Y, Tajika M, Kato M, Fukushima H, Shiraki M: Branched-chain amino acids as a protein- and energy-source in liver cirrhosis. Biochem Biophys Res Commun 2004;313:405–409.
Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, Rossi Fanelli F, Abbiati R: Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology 2003;124:1792–1801.
Muto Y, Sato S, Watanabe A, Moriwaki H, Suzuki K, Kato A, Kato M, Nakamura T, Higuchi K, Nishiguchi S, et al: Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol 2005;3:705–713.
Kumada H, Okanoue T, Onji M, Moriwaki H, Izumi N, Tanaka E, Chayama K, Sakisaka S, Takehara T, Oketani M, et al: Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis C virus infection for the fiscal year 2008 in Japan. Hepatol Res 2010;40:8–13.
Hayaishi S, Chung H, Kudo M, Ishikawa E, Takita M, Ueda T, Kitai S, Inoue T, Yada N, Hagiwara S, et al: Oral branched-chain amino acid granules reduce the incidence of hepatocellular carcinoma and improve event-free survival in patients with liver cirrhosis. Dig Dis 2011;29:326–332.
Fan ST, Lo CM, Lai EC, Chu KM, Liu CL, Wong J: Perioperative nutritional support in patients undergoing hepatectomy for hepatocellular carcinoma. N Engl J Med 1994;331:1547–1552.
Okabayashi T, Nishimori I, Sugimoto T, Maeda H, Dabanaka K, Onishi S, Kobayashi M, Hanazaki K: Effects of branched-chain amino acids-enriched nutrient support for patients undergoing liver resection for hepatocellular carcinoma. J Gastroenterol Hepatol 2008;23:1869–1873.
Poon RT, Yu WC, Fan ST, Wong J: Long-term oral branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma: a randomized trial. Aliment Pharmacol Ther 2004;19:779–788.
Holecek M: Three targets of branched-chain amino acid supplementation in the treatment of liver disease. Nutrition 2010;26:482–490.
Tomiya T, Omata M, Fujiwara K: Significance of branched chain amino acids as possible stimulators of hepatocyte growth factor. Biochem Biophys Res Commun 2004;313:411–416.
Calder PC: Branched-chain amino acids and immunity. J Nutr 2006;136(suppl):288S–293S.
Kakazu E, Ueno Y, Kondo Y, Fukushima K, Shiina M, Inoue J, Tamai K, Ninomiya M, Shimosegawa T: Branched chain amino acids enhance the maturation and function of myeloid dendritic cells ex vivo in patients with advanced cirrhosis. Hepatology 2009;50:1936–1945.
Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M, Rodes J: Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona 2000 EASL Conference. European Association for the Study of the Liver. J Hepatol 2001;35:421–430.
Bruix J, Sherman M: Management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236.
Bruix J, Sherman M: Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020–1022.
Group formed to establish ‘Guidelines for Evidence-Based Clinical Practice for the Treatment of Liver Cancer’: Clinical Practice Guidelines for Hepatocellular Carcinoma (in Japanese). Tokyo, Kanehara, 2005.
Makuuchi M, Kokudo N, Arii S, Igaki H, Ikai I, Kaneko S, Kawasaki S, Kudo M, Matsuyama Y, Ohtomo K, et al: Surveillance algorithm and diagnostic algorithm for hepatocellular carcinoma. Hepatol Res 2010;40 (suppl 1):1–144.
Makuuchi M, Kokudo N: Clinical practice guidelines for hepatocellular carcinoma: the first evidence-based guidelines from Japan. World J Gastroenterol 2006;12:828–829.
Kokudo N, Sasaki Y, Nakayama T, Makuuchi M: Dissemination of evidence-based clinical practice guidelines for hepatocellular carcinoma among Japanese hepatologists, liver surgeons and primary care physicians. Gut 2007;56:1020–1021.
Expert Panel of Japan Society of Hepatology: Clinical Practice Manual for Hepatocellular Carcinoma (in Japanese). Tokyo, Igaku-Shoin, 2007.
Kudo M, Okanoue T; Japan Society of Hepatology: Management of hepatocellular carcinoma in Japan: Consensus-based clinical practice manual proposed by the Japan Society of Hepatology. Oncology 2007;72(suppl 1):2–15.
Japan Society of Hepatology: Consensus-Based Clinical Practice Manual of Hepatocellular Carcinoma, ed 2 (in Japanese). Tokyo, Igaku-Shoin, 2010.
Kudo M, Izumi N, Kokudo N, et al: Management of hepatocellular carcinoma in Japan: Consensus-based clinical practice guidelines proposed by the Japan Soceity of Hepatology (JSH) 2010 updated version. Dig Dis 2011;29:339–364.
Arii S, Sata M, Sakamoto M, Shimada M, Kumada T, Shiina S, Yamashita T, Kokudo N, Tanaka M, Takayama T, et al: Management of Hepatocellular Carcinoma: Report of Consensus Meeting in the 45th Annual Meeting of the Japan Society of Hepatology (2009). Hepatol Res 2010;40:667–685.
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