Hepatocellular Carcinoma

Abstract

Primary liver cancer is the third leading cause of cancer‐related deaths and fifth most common cancer in the world. Globally, estimated 877 000 people develop liver cancer and an almost equal number die of it in 2007. The worldwide prevalence, unique geographic distribution and well‐established aetiologic factors of hepatocellular carcinoma (HCC) have provided a strong impetus for elucidating mechanisms underlying the development of this aggressive malignancy. A better understanding of the specific molecular features of hepatocarcinogenesis has revealed clues for novel preventative and therapeutic strategies. Of particular note, the recent extraordinary progress in the genetic and genomic understanding of this disease may shed light on the molecular mechanisms of HCC progression and this knowledge may offer great opportunities for improving the treatment and prevention of HCC.

Key Concepts:

  • HBV, HCV, alcohol, aflatoxin, diabetes and obesity constitute the main risk factors for HCC.

  • Prediction of prognosis and response to therapy, screening of high‐risk cases and science‐based therapy are the challenging tasks to improve clinical medicine.

  • HCC is a highly heterogeneous disease, which exists between primary tumours from different individuals as well as within a single carcinoma, where subpopulation can range from primitive, stem‐like cells to foci of well‐differentiated malignant epithelium.

  • Both genetic and epigenetic changes contribute to HCC, the understanding of mechanisms behind those changes may lead to personalised HCC medicine.

Keywords: HBV; HCV; p53; genomics; miRNAs; DNA methylation; cancer stem cells

Figure 1.

Model of multistage hepatocellular carcinogenesis. HBx, HBV X protein; AFB1, aflatoxin B1.

Figure 2.

Clinical management of hepatocellular carcinoma (HCC). Currently only about 10–30% patients presenting with HCC are eligible for surgical invention [hepatic resection (HR) or liver transplantation (LT)]. For the majority of HCC patients, treatment options are limited to palliative care or the administration of local/regional therapies such as radio frequency ablation (RFA) or percutaneous ethanol injection (PEI) TACE, transcatheter arterial chemoembolisation.

Figure 3.

Model of the parallels between hepatocellular carcinoma (HCC) subtypes and normal human liver cell lineage. EpCAM+AFP+HCC, hepatic stem cell‐like HCC; HpSC‐HCC; EpCAM+AFP–HCC, bile duct epithelium‐like HCC; BDE‐HCC; EpCAMAFP+HCC, hepatocytic progenitor‐like HCC; HP‐HCC; EpCAMAFPHCC, mature hepatocyte‐like HCC; MH‐HCC.

Figure 4.

Signalling pathways altered in hepatic cancer cells. Multiple signal transduction pathways are operational in liver cancer cells (whether the tumour consists of stem‐like cells and/or more differentiated subpopulations), many of which converge influencing cellular proliferation, growth, survival and differentiation (Kumar et al., ).

close

References

Aguilar F, Hussain SP and Cerutti P (1993) Aflatoxin B1 induces the transversion of G→T in codon 249 of the p53 tumor suppressor gene in human hepatocytes. Proceedings of the National Academy of Sciences of the USA 90: 8586–8590.

Bergsland EK (2001) Molecular mechanisms underlying the development of hepatocellular carcinoma. Seminars in Oncology 28: 521–531.

Budhu A, Jia HL, Forgues M et al. (2008) Identification of metastasis‐related microRNAs in hepatocellular carcinoma. Hepatology 47: 897–907.

Chang MH, Chen CJ, Lai MS et al. (1997) Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. New England Journal of Medicine 336: 1855–1859.

Curley SA, Izzo F, Gallipoli A et al. (1995) Identification and screening of 416 patients with chronic hepatitis at high risk to develop hepatocellular cancer. Annals of Surgery 222: 375–380.

Filipowicz W and Grosshans H (2011) The liver‐specific microRNA miR‐122: biology and therapeutic potential. Progress in Drug Research 67: 221–238.

Gramantieri L, Fornari F, Callegari E et al. (2008) MicroRNA involvement in hepatocellular carcinoma. Journal of Cellular and Molecular Medicine 12: 2189–2204.

Homayounfar K, Gunawan B, Cameron S et al. (2009) Pattern of chromosomal aberrations in primary liver cancers identified by comparative genomic hybridization. Human Pathology 40: 834–842.

Hong H, Takahashi K, Ichisaka T et al. (2009) Suppression of induced pluripotent stem cell generation by the p53–p21 pathway. Nature 460: 1132–1135.

Hoshida Y, Nijman SM, Kobayashi M et al. (2009) Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Research 69: 7385–7392.

Hoshida Y, Villanueva A, Kobayashi M et al. (2008) Gene expression in fixed tissues and outcome in hepatocellular carcinoma. New England Journal of Medicine. 359: 1995–2004.

Huang J (2009) Current progress in epigenetic research for hepatocarcinomagenesis. Science in China Series C Life Sciences 52: 31–42.

Ji J, Shi J, Budhu A et al. (2009) MicroRNA expression, survival, and response to interferon in liver cancer. New England Journal of Medicine 361: 1437–1447.

Kirk GD, Lesi OA, Mendy M et al. (2005) 249(ser) TP53 mutation in plasma DNA, hepatitis B viral infection, and risk of hepatocellular carcinoma. Oncogene 24: 5858–5867.

Kota J, Chivukula RR, O'donnell KA et al. (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137: 1005–1017.

Kumar M, Zhao X and Wang XW (2011) Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine? Cell & Bioscience 1: 5.

Laurent‐Puig P, Legoix P, Bluteau O et al. (2001) Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology 120: 1763–1773.

Lee JS, Chu IS, Heo J et al. (2004) Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 40: 667–676.

Lee JS, Heo J, Libbrecht L et al. (2006) A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nature Medicine 12: 410–416.

Lewis AP and Jopling CL (2010) Regulation and biological function of the liver‐specific miR‐122. Biochemical Society Transactions 38: 1553–1557.

Mao Y, Yang H, Xu H et al. (2010) Golgi protein 73 (GOLPH2) is a valuable serum marker for hepatocellular carcinoma. Gut 59: 1687–1693.

Murakami Y, Saigo K, Takashima H et al. (2005) Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut 54: 1162–1168.

Ozturk M (1999) Genetic aspects of hepatocellular carcinogenesis. Seminars in Liver Disease 19: 235–242.

Porta C and Paglino C (2010) Medical treatment of unresectable hepatocellular carcinoma: going beyond sorafenib. World Journal of Hepatology 2: 103–113.

Roessler S, Budhu A and Wang XW (2007) Future of molecular profiling of human hepatocellular carcinoma. Future Oncology 3: 429–439.

Roessler S, Jia HL, Budhu A et al. (2010) A unique metastasis gene signature enables prediction of tumor relapse in early stage hepatocellular carcinoma patients. Cancer Research 70: 10202–10212.

Shin SH, Kim BH, Jang JJ, Suh KS and Kang GH (2010) Identification of novel methylation markers in hepatocellular carcinoma using a methylation array. Journal of Korean Medical Science 25: 1152–1159.

Taketa K (1990) Alpha‐fetoprotein: reevaluation in hepatology. Hepatology 12: 1420–1432.

Thomas MB, Jaffe D, Choti MM et al. (2010) Hepatocellular carcinoma: consensus recommendations of the National Cancer Institute Clinical Trials Planning Meeting. Journal of Clinical Oncology 28: 3994–4005.

Thorgeirsson SS and Grisham JW (2002) Molecular pathogenesis of human hepatocellular carcinoma. Nature Genetics 31: 339–346.

Woo HG, Wang XW, Budhu A et al. (2011) Association of TP53 mutations with stem cell‐like gene expression s of patients with hepatocellular carcinoma. Gastroenterology 140: 1063–1070.

Yamashita T, Forgues M, Wang W et al. (2008) EpCAM and alpha‐fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Research 68: 1451–1461.

Ye QH, Qin LX, Forgues M et al. (2003) Predicting hepatitis B virus‐positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nature Genetics 9: 416–423.

Zhang G, Wang Q and Xu R (2010) Therapeutics based on microRNA: a new approach for liver cancer. Current Genomics 11: 311–325.

Zhu J (2006) DNA methylation and hepatocellular carcinoma. Journal of Hepato‐Biliary‐Pancreatic Surgery 13: 265–273.

Further Reading

Anthony PP (2001) Hepatocellular carcinoma: an overview. Histopathology 39: 109–118.

Montesano R, Hainaut P and Wild CP (1997) Hepatocellular carcinoma: from gene to public health. Journal of the National Cancer Institute 89: 1844–1851.

Monto A and Wright TL (2001) The epidemiology and prevention of hepatocellular carcinoma. Seminars in Oncology 28: 441–449.

Okabe H, Satoh S, Kato T et al. (2001) Genome‐wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Research 61: 2129–2137.

Wang XW and Thorgeirsson SS (2009) Transcriptome analysis of liver cancer: ready for the clinic? Journal of Hepatology 50: 1062–1064.

Wang XW, Grisham JW and Thorgeirsson SS (2011) Molecular Genetics of Liver Neoplasia, Cancer Genetics. New York: Springer.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Zhao, Xuelian, Elmore, Lynne W, Harris, Curtis C, and Wang, Xin Wei(Jul 2011) Hepatocellular Carcinoma. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006112.pub2]