Abstract
Persistent inflammation is known to promote and exacerbate malignancy. Primary liver cancer, mostly hepatocellular carcinoma (HCC), is a clear example of inflammation-related cancer as more than 90 % of HCCs arise in the context of hepatic injury and inflammation. HCC represents the fifth most common malignancy and the third leading cause of cancer-related death worldwide with about one million new cases diagnosed every year with almost an equal number of deaths. Chronic unresolved inflammation is associated with persistent hepatic injury and concurrent regeneration, leading to sequential development of fibrosis, cirrhosis, and eventually HCC. Irrespective of the intrinsic differences among various etiological factors, a common denominator at the origin of HCC is the perpetuation of a wound-healing response activated by parenchymal cell death and the resulting inflammatory cascade. Hence, the identification of fundamental inflammatory signaling pathways causing transition from chronic liver injury to dysplasia and HCC could depict new predictive biomarkers and targets to identify and treat patients with chronic liver inflammation. This chapter critically discusses the roles of several major cytokines, chemokines, growth factors, transcription factors, and enzymes as well as a distinct network of inflammatory signaling pathways in the development and progression of HCC. It also highlights and analyzes preclinical animal studies showing innovative approaches of targeting inflammatory mediators and signaling by a variety of natural compounds and synthetic agents to achieve effective therapy as well as prevention of hepatic malignancy. Additionally, current limitations and potential challenges associated with the inhibition of inflammatory signaling as well as future directions of research to accelerate clinical development of anti-inflammatory agents to prevent and treat liver cancer are presented.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Aggarwal BB, Sung B (2011) NF-κB in cancer: a matter of life and death. Cancer Discov 1:469–471
Ahn B, Han BS, Kim DJ, Ohshima H (1999) Immunohistochemical localization of inducible nitric oxide synthase and 3-nitrotyrosine in rat liver tumors induced by N-nitrosodiethylamine. Carcinogenesis 20:1337–1344
Alwahaibi NY, Budin SB, Mohamed J, Alhamdani A (2010) Nuclear factor-kappa B as a promising target for selenium chemoprevention in rat hepatocarcinogenesis. J Gastroenterol Hepatol 25:786–791
Aravalli RN, Steer CJ, Cressman EN (2008) Molecular mechanisms of hepatocellular carcinoma. Hepatology 48:2047–2063
Aravalli RN, Cressman EN, Steer CJ (2013) Cellular and molecular mechanisms of hepatocellular carcinoma: an update. Arch Toxicol 87:227–247
Aravindaram K, Yang NS (2010) Anti-inflammatory plant natural products for cancer therapy. Planta Med 76:1103–1117
Arsura M, Cavin LG (2005) Nuclear factor-kappaB and liver carcinogenesis. Cancer Lett 229:157–169
Avila MA, Berasain C, Sangro B, Prieto J (2006) New therapies for hepatocellular carcinoma. Oncogene 25:3866–3884
Bard-Chapeau EA, Li S, Ding J, Zhang SS, Zhu HH, Princen F, Fang DD, Han T, Bailly-Maitre B, Poli V, Varki NM, Wang H, Feng GS (2011) Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. Cancer Cell 19:629–639
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297
Bartsch H, Montesano R (1984) Relevance of nitrosamines to human cancer. Carcinogenesis 5:1381–1393
Berasain C, García-Trevijano ER, Castillo J, Erroba E, Lee DC, Prieto J, Avila MA (2005) Amphiregulin: an early trigger of liver regeneration in mice. Gastroenterology 128:424–432
Berasain C, Castillo J, Prieto J, Avila MA (2007) New molecular targets for hepatocellular carcinoma: the ErbB1 signaling system. Liver Int 27:174–185
Berasain C, Castillo J, Perugorria MJ, Latasa MU, Prieto J, Avila MA (2009a) Inflammation and liver cancer: new molecular links. Ann N Y Acad Sci 1155:206–221
Berasain C, Perugorria MJ, Latasa MU, Castillo J, Goñi S, Santamaría M, Prieto J, Avila MA (2009b) The epidermal growth factor receptor: a link between inflammation and liver cancer. Exp Biol Med 234:713–725
Bishayee A (2009) Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prev Res 2:409–418
Bishayee A (2012) Editorial: recent advances in the prevention and therapy of hepatocellular carcinoma. Curr Cancer Drug Targets 12:1043–1044
Bishayee A (2013) β-Catenin: a novel biomarker and therapeutic target in liver cancer. In: Georgakilas A (ed) Cancer biomarkers. CRC Press, Boca Raton, pp 51–75
Bishayee A, Dhir N (2009) Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: inhibition of cell proliferation and induction of apoptosis. Chem Biol Interact 179:131–144
Bishayee A, Politis T, Darvesh AS (2010a) Resveratrol in the chemoprevention and treatment of hepatocellular carcinoma. Cancer Treat Rev 36:43–53
Bishayee A, Waghray A, Barnes KF, Mbimba T, Bhatia D, Chatterjee M, Darvesh AS (2010b) Suppression of the inflammatory cascade is implicated in resveratrol chemoprevention of experimental hepatocarcinogenesis. Pharm Res 27:1080–1091
Bishayee A, Barnes KF, Bhatia D, Darvesh AS, Carroll RT (2010c) Resveratrol suppresses oxidative stress and inflammatory response in diethylnitrosamine-initiated rat hepatocarcinogenesis. Cancer Prev Res 3:753–763
Bishayee A, Mbimba T, Thoppil RJ, Háznagy-Radnai E, Sipos P, Darvesh AS, Folkesson H, Hohmann J (2011a) Anthocyanin-rich black currant (Ribes nigrum L.) extract affords chemoprevention against diethylnitrosamine-induced hepatocellular carcinogenesis in rats. J Nutr Biochem 22:1035–1046
Bishayee A, Bhatia D, Thoppil RJ, Darvesh AS, Nevo E, Lansky EP (2011b) Pomegranate-mediated chemoprevention of experimental hepatocarcinogenesis involves Nrf2-regulated antioxidant mechanisms. Carcinogenesis 32:888–896
Bishayee A, Thoppil RJ, Waghray A, Kruse JA, Novotny NA, Darvesh AS (2012) Dietary phytochemicals in the chemoprevention and treatment of hepatocellular carcinoma: in vivo evidence, molecular targets, and clinical relevance. Curr Cancer Drug Targets 12:1191–1232
Bishayee A, Thoppil RJ, Mandal A, Darvesh AS, Ohanyan V, Meszaros JG, Háznagy-Radnai E, Hohmann J, Bhatia D (2013a) Black currant phytoconstituents exert chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis by suppression of the inflammatory response. Mol Carcinog 52:304–317
Bishayee A, Thoppil RJ, Darvesh AS, Ohanyan V, Meszaros JG, Bhatia D (2013b) Pomegranate phytoconstituents blunt the inflammatory cascade in a chemically induced rodent model of hepatocellular carcinogenesis. J Nutr Biochem 24:178–187
Blonski W, Kotlyar DS, Forde KA (2010) Non-viral causes of hepatocellular carcinoma. World J Gastroenterol 16:3603–3615
Braconi C, Henry JC, Kogure T, Schmittgen T, Patel T (2011) The role of microRNAs in human liver cancers. Semin Onccol 38:752–763
Brownell J, Polyak SJ (2013) Molecular pathways: hepatitis C virus, CXCL10, and the inflammatory road to liver cancer. Clin Cancer Res 19:1347–1352
Budhu A, Wang XW (2006) The role of cytokines in hepatocellular carcinoma. J Leukoc Biol 80:1197–1213
Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, Factor VM, Thorgeirsson SS (2006) Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 130:1117–1128
Calvisi DF, Pinna F, Ladu S, Pellegrino R, Muroni MR, Simile MM, Frau M, Tomasi ML, De Miglio MR, Seddaiu MA, Daino L, Sanna V, Feo F, Pascale RM (2008) Aberrant iNOS signaling is under genetic control in rodent liver cancer and potentially prognostic for the human disease. Carcinogenesis 29:1639–1647
Castillo J, Erroba E, Perugorría MJ, Santamaría M, Lee DC, Prieto J, Avila MA, Berasain C (2006) Amphiregulin contributes to the transformed phenotype of human hepatocellular carcinoma cells. Cancer Res 66:6129–6138
Center MM, Jemal A (2011) International trends in liver cancer incidence rates. Cancer Epidemiol Biomarkers Prev 20:2362–2368
Cervello M, Montalto G (2006) Cyclooxygenases in hepatocellular carcinoma. World J Gastroenterol 12:5113–5121
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10:25–34
Chiang SH, Bazuine M, Lumeng CN, Geletka LM, Mowers J, White NM, Ma JT, Zhou J, Qi N, Westcott D, Delproposto JB, Blackwell TS, Yull FE, Saltiel AR (2009) The protein kinase IKKepsilon regulates energy balance in obese mice. Cell 138:961–975
Chuang SE, Cheng AL, Lin JK, Kuo ML (2000) Inhibition by curcumin of diethylnitrosamine-induced hepatic hyperplasia, inflammation, cellular gene products and cell-cycle-related proteins in rats. Food Chem Toxicol 38:991–995
Chuma M, Hige S, Nakanishi M, Ogawa K, Natsuizaka M, Yamamoto Y, Asaka M (2008) 8-Hydroxy-2’-deoxy-guanosine is a risk factor for development of hepatocellular carcinoma in patients with chronic hepatitis C virus infection. J Gastroenterol Hepatol 23:1431–1436
Costa RH, Kalinichenko VV, Holterman AX, Wang X (2003) Transcription factors in liver development, differentiation, and regeneration. Hepatology 38:1331–1347
Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867
Cui W, Gu F, Hu K (2009) Effects and mechanisms of silibinin on human hepatocellular carcinoma xenografts in nude mice. World J Gastroenterol 15:1943–1950
Dajani OF, Meisdalen K, Guren TK, Aasrum M, Tveteraas IH, Lilleby P, Thoresen GH, Sandnes D, Christoffersen T (2008) Prostaglandin E2 upregulates EGF-stimulated signaling in mitogenic pathways involving Akt and ERK in hepatocytes. J Cell Physiol 214:371–380
Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415–1421
Darvesh AS, Bishayee A (2010) Selenium in the prevention and treatment of hepatocellular carcinoma. Anticancer Agents Med Chem 10:338–345
Darvesh AS, Bishayee A (2013) Chemopreventive and therapeutic potential of tea polyphenols in hepatocellular cancer. Nutr Cancer 65:329–344
Darvesh AS, Aggarwal BB, Bishayee A (2012) Curcumin and liver cancer: a review. Curr Pharm Biotechnol 13:218–228
Davies RA, Knight B, Tian YW, Yeoh GC, Olynyk JK (2006) Hepatic oval cell response to the choline-deficient, ethionine supplemented model of murine liver injury is attenuated by the administration of a cyclo-oxygenase 2 inhibitor. Carcinogenesis 27:1607–1616
de Almagro MC, Vucic D (2012) The inhibitor of apoptosis (IAP) proteins are critical regulators of signaling pathways and targets for anti-cancer therapy. Exp Oncol 34:200–211
Denda A, Kitayama W, Murata A, Kishida H, Sasaki Y, Kusuoka O, Tsujiuchi T, Tsutsumi M, Nakae D, Takagi H, Konishi Y (2002) Increased expression of cyclooxygenase-2 protein during rat hepatocarcinogenesis caused by a choline-deficient, L-amino acid-defined diet and chemopreventive efficacy of a specific inhibitor, nimesulide. Carcinogenesis 23:245–256
Denda A, Kitayama W, Kishida H, Murata N, Tamura K, Kusuoka O, Tsutsumi M, Nishikawa F, Kita E, Nakae D, Konishi Y, Kuniyasu H (2007) Expression of inducible nitric oxide (NO) synthase but not prevention by its gene ablation of hepatocarcinogenesis with fibrosis caused by a choline-deficient, L-amino acid-defined diet in rats and mice. Nitric Oxide 16:164–176
Demaria S, Pikarsky E, Karin M, Coussens LM, Chen YC, El-Omar EM, Trinchieri G, Dubinett SM, Mao JT, Szabo E, Krieg A, Weiner GJ, Fox BA, Coukos G, Wang E, Abraham RT, Carbone M, Lotze MT (2010) Cancer and inflammation: promise for biologic therapy. J Immunother 33:335–351
Deviere J, Content J, Denys C, Vandenbussche P, Schandene L, Wybran J, Dupont E (1989) High interleukin-6 serum levels and increased production by leucocytes in alcoholic liver cirrhosis. Correlation with IgA serum levels and lymphokines production. Clin Exp Immunol 77:221–225
Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11:98–107
DiDonato JA, Mercurio F, Karin M (2012) NF-κB and the link between inflammation and cancer. Immunol Rev 246:379–400
Dutkowski P, De Rougemont O, Müllhaupt B, Clavien PA (2010) Current and future trends in liver transplantation in Europe. Gastroenterology 138:802–809
El-Serag HB (2004) Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 127:S27–S34
El-Serag HB, Hampel H, Javadi F (2006) The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 4:369–380
El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132:2557–2576
Espindola RM, Mazzantini RP, Ong TP, de Conti A, Heidor R, Moreno FS (2005) Geranylgeraniol and β-ionone inhibit hepatic preneoplastic lesions, cell proliferation, total plasma cholesterol and DNA damage during the initial phases of hepatocarcinogenesis, but only the former inhibits NF-κB activation. Carcinogenesis 26:1091–1099
Farazi PA, DePinho RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6:674–687
Futakuchi M, Ogawa K, Sano M, Tamano S, Takeshita F, Shirai T (2002) Suppression of lung metastasis by aspirin but not indomethacin in an in vivo model of chemically induced hepatocellular carcinoma. Jpn J Cancer Res 93:1175–1181
Gao J, Xie L, Yang WS, Zhang W, Gao S, Wang J, Xiang YB (2012) Risk factors of hepatocellular carcinoma: current status and perspectives. Asian Pac J Cancer Prev 13:743–752
Ghosh S, Karin M (2002) Missing pieces in the NF-κB puzzle. Cell 109:S81–S96
Giannitrapani L, Ingrao S, Soresi M, Florena AM, La Spada E, Sandonato L, D’Alessandro N, Cervello M, Montalto G (2009) Cyclooxygenase-2 expression in chronic liver diseases and hepatocellular carcinoma: an immunohistochemical study. Ann NY Acad Sci 1155:293–299
Gramantieri L, Fornari F, Callegari E, Sabbioni S, Lanza G, Croce CM, Bolondi L, Negrini M (2008) MicroRNA involvement in hepatocellular carcinoma. J Cell Mol Med 12:2189–2204
Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445
Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899
Gupta SC, Kim JH, Prasad S, Aggarwal BB (2010) Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals. Cancer Metastasis Rev 29:405–434
Guicciardi ME, Mott JL, Bronk SF, Kurita S, Fingas CD, Gores GJ (2011) Cellular inhibitor of apoptosis 1 (cIAP-1) degradation by caspase 8 during TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Exp Cell Res 317:107–116
Gyrd-Hansen M, Meier P (2010) IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat Rev Cancer 10:561–574
Han YP, Zhou L, Wang J, Xiong S, Garner WL, French SW, Tsukamoto H (2004) Essential role of matrix metalloproteinases in interleukin-1-induced myofibroblastic activation of hepatic stellate cell in collagen. J Biol Chem 279:4820–4828
Han C, Michalopoulos GK, Wu T (2006) Prostaglandin E2 receptor EP1 transactivates EGFR/MET receptor tyrosine kinases and enhances invasiveness in human hepatocellular carcinoma cells. J Cell Physiol 207:261–270
Hatziapostolou M, Polytarchou C, Aggelidou E, Drakaki A, Poultsides GA, Jaeger SA, Ogata H, Karin M, Struhl K, Hadzopoulou-Cladaras M, Iliopoulos D (2011) An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell 147:1233–1247
Haybaeck J, Zeller N, Wolf MJ, Weber A, Wagner U, Kurrer MO, Bremer J, Iezzi G, Graf R, Clavien PA, Thimme R, Blum H, Nedospasov SA, Zatloukal K, Ramzan M, Ciesek S, Pietschmann T, Marche PN, Karin M, Kopf M, Browning JL, Aguzzi A, Heikenwalder M (2009) A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 16:295–308
Heydtmann M, Adams DH (2009) Chemokines in the immunopathogenesis of hepatitis C infection. Hepatology 49:676–688
He G, Karin M (2011) NF-κB and STAT3: key players in liver inflammation and cancer. Cell Res 21:159–168
He G, Yu GY, Temkin V, Ogata H, Kuntzen C, Sakurai T, Sieghart W, Peck-Radosavljevic M, Leffert HL, Karin M (2010) Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17:286–297
Hoffmann A, Baltimore D (2006) Circuitry of nuclear factor kappaB signaling. Immunol Rev 210:171–186
Hoshida Y, Toffanin S, Lachenmayer A, Villanueva A, Minguez B, Llovet JM (2010) Molecular classification and novel targets in hepatocellular carcinoma: recent advancements. Semin Liver Dis 30:35–51
Huang F, Geng XP (2010) Chemokines and hepatocellular carcinoma. World J Gastroenterol 16:1832–1836
Huynh H (2010) Molecularly targeted therapy in hepatocellular carcinoma. Biochem Pharmacol 80:550–560
Je Y, Schutz FAB, Choueiri TK (2009) Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. Lancet Oncol 10:967–974
Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S, Ambs S, Chen Y, Meltzer PS, Croce CM, Qin LX, Man K, Lo CM, Lee J, Ng IO, Fan J, Tang ZY, Sun HC, Wang XW (2009) MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med 361:1437–147
Karin M (2009) NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol 1:a000141
Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol 18:621–663
Kawanishi S, Hiraku Y, Pinlaor S, Ma N (2006) Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis. Biol Chem 387:365–372
Kenya PR (1990) Oral contraceptives use and liver tumours: a review. East Afr Med J 67:146–153
Khan MS, Devaraj H, Devaraj N (2011) Chrysin abrogates early hepatocarcinogenesis and induces apoptosis in N-nitrosodiethylamine-induced preneoplastic nodules in rats. Toxicol Appl Pharmacol 251:85–94
Kim SF, Huri DA, Snyder SH (2005) Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science 310:1966–1970
Kim YS, Young MR, Bobe G, Colburn NH, Milner JA (2009) Bioactive food components, inflammatory targets, and cancer prevention. Cancer Prev Res 2:200–208
Kota J, Chivukula RR, O’Donnell KA, Wentzel EA, Montgomery CL, Hwang HW, Chang TC, Vivekanandan P, Torbenson M, Clark KR, Mendell JR, Mendell JT (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137:1005–1017
Kuo PC, Abe KY, Schroeder RA (1997) Oxidative stress increases hepatocyte iNOS gene transcription and promoter activity. Biochem Biophys Res Commun 234:289–292
Korula J, Yellin A, Kanel G, Campofiori G, Nichols P (1991) Hepatocellular carcinoma coexisting with hepatic adenoma. Incidental discovery after long-term oral contraceptive use. West J Med 155:416–418
Lachenmayer A, Alsinet C, Chang CY, Llovet JM (2010) Molecular approaches to treatment of hepatocellular carcinoma. Dig Liver Dis 42:S264–S272
Lang K, Danchenko N, Gondek K, Shah S, Thompson D (2009) The burden of illness associated with hepatocellular carcinoma in the United States. J Hepatol 50:89–99
Larsson SC, Wolk A (2007) Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer 97:1005–1008
Lee Y, Park US, Choi I, Yoon SK, Park YM, Lee YI (1998) Human interleukin 6 gene is activated by hepatitis B virus-X protein in human hepatoma cells. Clin Cancer Res 4:1711–1717
Lee H, Herrmann A, Deng JH, Kujawski M, Niu G, Li Z, Forman S, Jove R, Pardoll DM, Yu H (2009) Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell 15:283–293
Liu W, Nakamura H, Tsujimura T, Cheng J, Yamamoto T, Iwamoto Y, Imanishi H, Shimomura S, Yamamoto T, Hirasawa T, Inagaki S, Nishiguchi S, Hada T (2006) Chemoprevention of spontaneous development of hepatocellular carcinomas in fatty liver Shionogi mice by a cyclooxygenase-2 inhibitor. Cancer Sci 97:768–773
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, SHARP Investigators Study Group (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390
Lu SC (2010) Where are we in the chemoprevention of hepatocellular carcinoma? Hepatology 51:734–736
Lu XL, He SX, Ren MD, Wang YL, Zhang YX, Liu EQ (2012) Chemopreventive effect of saikosaponin-d on diethylinitrosamine-induced hepatocarcinogenesis: involvement of CCAAT/enhancer binding protein β and cyclooxygenase-2. Mol Med Rep 5:637–644
Luedde T, Schwabe RF (2011) NF-κB in the liver: linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 8:108–118
Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, De Vos R, Roskams T, Trautwein C, Pasparakis M (2007) Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11:119–132
Ma Y, Wang J, Liu L, Zhu H, Chen X, Pan S, Sun X, Jiang H (2011) Genistein potentiates the effect of arsenic trioxide against human hepatocellular carcinoma: role of Akt and nuclear factor-κB. Cancer Lett 301:75–84
Maeda S, Kamata H, Luo JL, Leffert H, Karin M (2005) IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121:977–990
Maeda S, Hikiba Y, Sakamoto K, Nakagawa H, Hirata Y, Hayakawa Y, Yanai A, Ogura K, Karin M, Omata M (2009) Ikappa B kinasebeta/nuclear factor-kappaB activation controls the development of liver metastasis by way of interleukin-6 expression. Hepatology 50:1851–1860
Maione D, Di Carlo E, Li W, Musiani P, Modesti A, Peters M, Rose-John S, Della Rocca C, Tripodi M, Lazzaro D, Taub R, Savino R, Ciliberto G (1998) Coexpression of IL-6 and soluble IL-6R causes nodular regenerative hyperplasia and adenomas of the liver. EMBO J 17:5588–5597
Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444
Markiewski MM, DeAngelis RA, Lambris JD (2006) Liver inflammation and regeneration: two distinct biological phenomena or parallel pathophysiologic processes? Mol Immunol 43:45–56
Márquez-Rosado L, Trejo-Solís MC, García-Cuéllar CM, Villa-Treviño S (2005) Celecoxib, a cyclooxygenase-2 inhibitor, prevents induction of liver preneoplastic lesions in rats. J Hepatol 43:653–660
Marra M, Sordelli IM, Lombardi A, Lamberti M, Tarantino L, Giudice A, Stiuso P, Abbruzzese A, Sperlongano R, Accardo M, Agresti M, Caraglia M, Sperlongano P (2011) Molecular targets and oxidative stress biomarkers in hepatocellular carcinoma: an overview. J Transl Med 9:171
Marrero CR, Marrero JA (2007) Viral hepatitis and hepatocellular carcinoma. Arch Med Res 38:612–620
Matsuzaki K, Murata M, Yoshida K, Sekimoto G, Uemura Y, Sakaida N, Kaibori M, Kamiyama Y, Nishizawa M, Fujisawa J, Okazaki K, Seki T (2007) Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology 46:48–57
Mauad TH, van Nieuwkerk CM, Dingemans KP, Smit JJ, Schinkel AH, Notenboom RG, van den Bergh Weerman MA, Verkruisen RP, Groen AK, Oude Elferink RP et al (1994) Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. Am J Pathol 145:1237–1245
Mauriz JL, Linares P, Macias RI, Jorquera F, Honrado E, Olcoz JL, González P, González-Gallego J (2003) TNP-470 inhibits oxidative stress, nitric oxide production and nuclear factor kappa B activation in a rat model of hepatocellular carcinoma. Free Radic Res 37:841–848
Mbimba T, Awale P, Bhatia D, Geldenhuys WJ, Darvesh AS, Carroll RT, Bishayee A (2012) Alteration of hepatic proinflammatory cytokines is involved in the resveratrol-mediated chemoprevention of chemically-induced hepatocarcinogenesis. Curr Pharm Biotechnol 13:229–234
McNaughton L, Puttagunta L, Martinez-Cuesta MA, Kneteman N, Mayers I, Moqbel R, Hamid Q, Radomski MW (2002) Distribution of nitric oxide synthase in normal and cirrhotic human liver. Proc Natl Acad Sci USA 99:17161–17166
Mehrotra S, Languino LR, Raskett CM, Mercurio AM, Dohi T, Altieri DC (2010) IAP regulation of metastasis. Cancer Cell 17:53–64
Mills JJ, Chari RS, Boyer IJ, Gould MN, Jirtle RL (1995) Induction of apoptosis in liver tumors by the monoterpene perillyl alcohol. Cancer Res 55:979–983
Ming L, Thorgeirsson SS, Gail MH, Lu P, Harris CC, Wang N, Shao Y, Wu Z, Liu G, Wang X, Sun Z (2002) Dominant role of hepatitis B virus and cofactor role of aflatoxin in hepatocarcinogenesis in Qidong, China. Hepatology 36:1214–1220
Murakami A (2009) Chemoprevention with phytochemicals targeting inducible nitric oxide synthase. Forum Nutr 61:193–203
Muriel P (2009) NF-kappaB in liver diseases: a target for drug therapy. J Appl Toxicol 29:91–100
Murillo MM, Carmona-Cuenca I, Del Castillo G, Ortiz C, Roncero C, Sánchez A, Fernández M, Fabregat I (2007) Activation of NADPH oxidase by transforming growth factor-beta in hepatocytes mediates up-regulation of epidermal growth factor receptor ligands through a nuclear factor-kappaB-dependent mechanism. Biochem J 405:251–259
Murugan RS, Priyadarsini RV, Ramalingam K, Hara Y, Karunagaran D, Nagini S (2010) Intrinsic apoptosis and NF-κB signaling are potential molecular targets for chemoprevention by black tea polyphenols in HepG2 cells in vitro and in a rat hepatocarcinogenesis model in vivo. Food Chem Toxicol 48:3281–3287
Nakagawa H, Maeda S (2012) Inflammation- and stress-related signaling pathways in hepatocarcinogenesis. World J Gastroenterol 18:4071–4081
Nakagawa H, Maeda S, Yoshida H, Tateishi R, Masuzaki R, Ohki T, Hayakawa Y, Kinoshita H, Yamakado M, Kato N, Shiina S, Omata M (2009) Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: an analysis based on gender differences. Int J Cancer 125:2264–2269
Nair S, Mason A, Eason J, Loss G, Perrillo RP (2002) Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis? Hepatology 36:150–155
Naugler WE, Karin M (2008) The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med 14:109–119
Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317:121–124
Nejak-Bowen KN, Monga SP (2011) Beta-catenin signaling, liver regeneration and hepatocellular cancer: sorting the good from the bad. Semin Cancer Biol 21:44–58
Nishikawa-Ogawa M, Wanibuchi H, Morimura K, Kinoshita A, Nishikawa T, Hayashi S, Yano Y, Fukushima S (2006) N-acetylcysteine and S-methylcysteine inhibit MeIQx rat hepatocarcinogenesis in the post-initiation stage. Carcinogenesis 27:982–988
Nordenstedt H, White DL, El-Serag HB (2010) The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis 42:S206–S214
Ogata H, Kobayashi T, Chinen T, Takaki H, Sanada T, Minoda Y, Koga K, Takaesu G, Maehara Y, Iida M, Yoshimura A (2006) Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. Gastroenterology 131:179–193
Pahl HL (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18:6853–6866
Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H, Karin M (2010) Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140:197–208
Pfitzner E, Kliem S, Baus D, Litterst CM (2004) The role of STATs in inflammation and inflammatory diseases. Curr Pharm Des 10:2839–2850
Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431:461–466
Qian GS, Ross RK, Yu MC, Yuan JM, Gao YT, Henderson BE, Wogan GN, Groopman JD (1994) A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People’s Republic of China. Cancer Epidemiol Biomarkers Prev 3:3–10
Rahman MA, Dhar DK, Yamaguchi E, Maruyama S, Sato T, Hayashi H, Ono T, Yamanoi A, Kohno H, Nagasue N (2001) Coexpression of inducible nitric oxide synthase and COX-2 in hepatocellular carcinoma and surrounding liver: possible involvement of COX-2 in the angiogenesis of hepatitis C virus-positive cases. Clin Cancer Res 7:1325–1332
Ramakrishnan G, Raghavendran HRB, Vinodhkumar R, Devaki T (2006) Suppression of N-nitrosodiethylamine induced hepatocarcinogenesis by silymarin in rats. Chem-Biol Interact 161:104–114
Ramakrishnan G, Elinos-Báez CM, Jagan S, Augustine TA, Kamaraj S, Anandakumar P, Devaki T (2008) Silymarin downregulates COX-2 expression and attenuates hyperlipidemia during NDEA-induced rat hepatocellular carcinoma. Mol Cell Biochem 313:53–61
Rogers AB, Theve EJ, Feng Y, Fry RC, Taghizadeh K, Clapp KM, Boussahmain C, Cormier KS, Fox JG (2007) Hepatocellular carcinoma associated with liver-gender disruption in male mice. Cancer Res 67:11536–11546
Ruggieri A, Barbati C, Malorni W (2010) Cellular and molecular mechanisms involved in hepatocellular carcinoma gender disparity. Int J Cancer 127:499–504
Sakamoto T, Higaki Y, Hara M, Ichiba M, Horita M, Mizuta T, Eguchi Y, Yasutake T, Ozaki I, Yamamoto K, Onohara S, Kawazoe S, Shigematsu H, Koizumi S, Tanaka K (2008) Interaction between interleukin-1β-31T/C gene polymorphism and drinking and smoking habits on the risk of hepatocellular carcinoma among Japanese. Cancer Lett 271:98–104
Sakurai T, He G, Matsuzawa A, Yu GY, Maeda S, Hardiman G, Karin M (2008) Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14:156–165
Schneider-Merck T, Borbath I, Charette N, De Saeger C, Abarca J, Leclercq I, Horsmans Y, Stärkel P (2009) The Ras inhibitor farnesylthiosalicyclic acid (FTS) prevents nodule formation and development of preneoplastic foci of altered hepatocytes in rats. Eur J Cancer 45:2050–2060
Schütte K, Bornschein J, Malfertheiner P (2009) Hepatocellular carcinoma—epidemiological trends and risk factors. Dig Dis 27:80–92
Sengupta S, Bishayee A (2010) MicroRNAs in cancer therapy: from bench to bedside. Curr Cancer Ther Rev 6:157–162
Senn JJ, Klover PJ, Nowak IA, Mooney RA (2002) Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes 51:3391–3399
Senthil M, Mailey B, Leong L, Chung V, Yen Y, Chen YJ, Marx H, Kim J (2010) Liver-directed regional therapy in the multi-disciplinary management of hepatocellular cancer. Curr Cancer Ther Rev 6:19–25
Sherman M (2005) Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis 25:143–154
Shimizu M, Sakai H, Shirakami Y, Yasuda Y, Kubota M, Terakura D, Baba A, Ohno T, Hara Y, Tanaka T, Moriwaki H (2011a) Preventive effects of (-)-epigallocatechin gallate on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice. Cancer Prev Res 4:396–403
Shimizu M, Sakai H, Shirakami Y, Iwasa J, Yasuda Y, Kubota M, Takai K, Tsurumi H, Tanaka T, Moriwaki H (2011b) Acyclic retinoid inhibits diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BLKS/J- +(db)/+Lepr(db) mice. Cancer Prev Res 4:128–136
Shimizu M, Yasuda Y, Sakai H, Kubota M, Terakura D, Baba A, Ohno T, Kochi T, Tsurumi H, Tanaka T, Moriwaki H (2011c) Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice. BMC Cancer 11:281
Shimizu M, Tanaka T, Moriwaki H (2013) Obesity and hepatocellular carcinoma: targeting obesity-related inflammation for chemoprevention of liver carcinogenesis. Semin Immunopathol 35:191–202
Shiota G, Okubo M, Noumi T, Noguchi N, Oyama K, Takano Y, Yashima K, Kishimoto Y, Kawasaki H (1999) Cyclooxygenase-2 expression in hepatocellular carcinoma. Hepatogastroenterology 46:407–412
Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. Clin Invest 116:1793–1801
Sibilia M, Kroismayr R, Lichtenberger BM, Natarajan A, Hecking M, Holcmann M (2007) The epidermal growth factor receptor: from development to tumorigenesis. Differentiation 75:770–787
Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63:11–30
Silke J, Meier P (2013) Inhibitor of apoptosis (IAP) proteins-modulators of cell death and inflammation. Cold Spring Harb Perspect Biol 5: a008730
Simile MM, Pagnan G, Pastorino F, Brignole C, De Miglio MR, Muroni MR, Asara G, Frau M, Seddaiu MA, Calvisi DF, Feo F, Ponzoni M, Pascale RM (2005) Chemopreventive N-(4-hydroxyphenyl) retinamide (fenretinide) targets deregulated NF-κB and Mat1A genes in the early stages of rat liver carcinogenesis. Carcinogenesis 26:417–427
Sivaramakrishnan V, Niranjali Devaraj S (2009) Morin regulates the expression of NF-κB-p65, COX-2 and matrix metalloproteinases in diethylnitrosamine induced rat hepatocellular carcinoma. Chem Biol Interact 180:353–359
Sivaramakrishnan V, Niranjali Devaraj S (2010) Morin fosters apoptosis in experimental hepatocellular carcinogenesis model. Chem Biol Interact 183:284–292
Stärkel P, Charette N, Borbath I, Schneider-Merck T, De Saeger C, Abarca J, Leclercq I, Horsmans Y (2012) Ras inhibition in hepatocarcinoma by S-trans-trans-farnesylthiosalicyclic acid: association of its tumor preventive effect with cell proliferation, cell cycle events, and angiogenesis. Mol Carcinog 51:816–825
Subramaniam A, Shanmugam MK, Perumal E, Li F, Nachiyappan A, Dai X, Swamy SN, Ahn KS, Kumar AP, Tan BK, Hui KM, Sethi G (2013) Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma. Biochim Biophys Acta 1835:46–60
Sun B, Karin M (2012) Obesity, inflammation, and liver cancer. J Hepatol 56:704–713
Sung YK, Hwang SY, Kim JO, Bae HI, Kim JC, Kim MK (2004) The correlation between cyclooxygenase-2 expression and hepatocellular carcinogenesis. Mol Cells 17:35–38
Szabo G, Lippai D (2012) Molecular hepatic carcinogenesis: impact of inflammation. Dig Dis 30:243–248
Tanaka H, Fujita N, Sugimoto R, Urawa N, Horiike S, Kobayashi Y, Iwasa M, Ma N, Kawanishi S, Watanabe S, Kaito M, Takei Y (2008) Hepatic oxidative DNA damage is associated with increased risk for hepatocellular carcinoma in chronic hepatitis C. Br J Cancer 98:580–586
Taub R (2003) Hepatoprotection via the IL-6/Stat3 pathway. J Clin Invest 112:978–980
Thoppil RJ, Bhatia D, Barnes KF, Háznagy-Radnai E, Hohmann J, Darvesh AS, Bishayee A (2012) Black currant anthocyanins abrogate oxidative stress through Nrf2-mediated antioxidant mechanisms in a rat model of hepatocellular carcinoma. Curr Cancer Drug Targets 12:1244–1257
Ueno S, Aoki D, Kubo F, Hiwatashi K, Matsushita K, Oyama T, Maruyama I, Aikou T (2005) Roxithromycin inhibits constitutive activation of nuclear factor & #x03BA;B by diminishing oxidative stress in a rat model of hepatocellular carcinoma. Clin Cancer Res 11:5645–5650
Wai PY, Kuo PC (2012) Intersecting pathways in inflammation and cancer: hepatocellular carcinoma as a paradigm. World J Clin Oncol 10:15–23
Wang LY, Chen CJ, Zhang YJ, Tsai WY, Lee PH, Feitelson MA, Lee CS, Santella RM (1998) 4-Aminobiphenyl DNA damage in liver tissue of hepatocellular carcinoma patients and controls. Am J Epidemiol 147:315–323
Wang Y, Kato N, Hoshida Y, Yoshida H, Taniguchi H, Goto T, Moriyama M, Otsuka M, Shiina S, Shiratori Y, Ito Y, Omata M (2003) Interleukin-1β gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection. Hepatology 37:65–71
Wang Y, Ausman LM, Greenberg AS, Russell RM, Wang XD (2009a) Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine-initiated early hepatocarcinogenesis in rats. Int J Cancer 124:540–546
Wang B, Majumder S, Nuovo G, Kutay H, Volinia S, Patel T, Schmittgen TD, Croce C, Ghoshal K, Jacob ST (2009b) Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice. Hepatology 50:1152–1161
Wang Y, Ausman LM, Greenberg AS, Russell RM, Wang XD (2010) Dietary lycopene and tomato extract supplementations inhibit nonalcoholic steatohepatitis-promoted hepatocarcinogenesis in rats. Int J Cancer 126:1788–1796
Weber A, Boege Y, Reisinger F, Heikenwälder M (2011) Chronic liver inflammation and hepatocellular carcinoma: persistence matters. Swiss Med Wkly 141:w13197
Weinhold B, Rüther U (1997) Interleukin-6-dependent and -independent regulation of the human C-reactive protein gene. Biochem J 327:425–429
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808
West AP, Koblansky AA, Ghosh S (2006) Recognition and signaling by toll-like receptors. Annu Rev Cell Dev Biol 22:409–437
White LA, Menzin J, Korn JR, Friedman M, Lang K, Ray S (2012) Medical care costs and survival associated with hepatocellular carcinoma among the elderly. Clin Gastroenterol Hepatol 10:547–554
Whittaker S, Marais R, Zhu AX (2010) The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene 29:4989–5005
Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, Feldstein AE (2008) Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol 103:1372–1379
Williams CS, Mann M, DuBois RN (1999) The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 18:7908–7916
Wilson JF (2005) Liver cancer on the rise. Ann Intern Med 142:1029–1032
Wong VW, Yu J, Cheng AS, Wong GL, Chan HY, Chu ES, Ng EK, Chan FK, Sung JJ, Chan HL (2009) High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B. Int J Cancer 124:2766–2770
Wong CM, Kai AK, Tsang FH, Ng IO (2013) Regulation of hepatocarcinogenesis by microRNAs. Front Biosci 5:49–60
Wu T (2005) Cycloygenase-2 and prostaglandin signaling in cholangiocarcinoma. Biochim Biophys Acta 1755:135–150
Wu T (2006) Cyclooxygenase-2 in hepatocellular carcinoma. Cancer Treat Rev 32:28–44
Wunderlich FT, Luedde T, Singer S, Schmidt-Supprian M, Baumgartl J, Schirmacher P, Pasparakis M, Brüning JC (2008) Hepatic NF-κB essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proc Natl Acad Sci USA 105:1297–1302
Xiao C, Ghosh S (2005) NF-kappaB, an evolutionarily conserved mediator of immune and inflammatory responses. Adv Exp Med Biol 560:41–45
Yamamoto H, Kondo M, Nakamori S, Nagano H, Wakasa K, Sugita Y, Chang-De J, Kobayashi S, Damdinsuren B, Dono K, Umeshita K, Sekimoto M, Sakon M, Matsuura N, Monden M (2003) JTE-522, a cyclooxygenase-2 inhibitor, is an effective chemopreventive agent against rat experimental liver fibrosis. Gastroenterology 125:556–571
Yildirim Y, Ozyilkan O, Bilezikci B, Akcali Z, Haberal M (2008) Lack of influence of cyclooxygenese-2 expression in hepatocellular carcinomas on patient survival. Asian Pac J Cancer Prev 9:295–298
Yoshimura A, Naka T, Kubo M (2007) SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 7:454–465
Yoysungnoen P, Wirachwong P, Bhattarakosol P, Niimi H, Patumraj S (2006) Effects of curcumin on tumor angiogenesis and biomarkers, COX-2 and VEGF, in hepatocellular carcinoma cell-implanted nude mice. Clin Hemorheol Microcirc 34:109–115
Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809
Zhao X, Zhang JJ, Wang X, Bu XY, Lou YQ, Zhang GL (2008) Effect of berberine on hepatocyte proliferation, inducible nitric oxide synthase expression, cytochrome P450 2E1 and 1A2 activities in diethylnitrosamine- and phenobarbital-treated rats. Biomed Pharmacother 62:567–572
Acknowledgements
A part of our research on chemoprevention of liver cancer by anti-inflammatory phytoconstituents as presented in this review was carried out at the Northeast Ohio Medical University (Rootstown, OH). I sincerely apologize to those investigators whose contributions were not cited due to space limitation.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Basel
About this chapter
Cite this chapter
Bishayee, A. (2014). The Inflammation and Liver Cancer. In: Aggarwal, B., Sung, B., Gupta, S. (eds) Inflammation and Cancer. Advances in Experimental Medicine and Biology, vol 816. Springer, Basel. https://doi.org/10.1007/978-3-0348-0837-8_16
Download citation
DOI: https://doi.org/10.1007/978-3-0348-0837-8_16
Published:
Publisher Name: Springer, Basel
Print ISBN: 978-3-0348-0836-1
Online ISBN: 978-3-0348-0837-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)