The Advances in Molecular Biology of Hepatoblastoma: Implications for Diagnostic Pathology
Keywords:
hepatoblastoma, pediatric liver malignancy, canonical Wnt/beta-catenin signaling pathway, hepatocyte growth factor (HGF)/c-Met signaling pathway, Notch signaling pathway, Hedgehog signaling pathwayAbstract
As the most common pediatric liver malignancy, hepatoblastoma (HB) accounts for more than 90% of primary hepatic malignant tumors in children less than five years of age in the US, and its incidence has been increasing in the past decades. Despite extensive studies, the pathogenesis of HB remains to be elucidated. Multiple signaling pathways may be involved in the oncogenic process of HB. The best characterized pathways include the canonical Wnt/beta-catenin pathway, the hepatocyte growth factor (HGF)/c-Met signaling pathway, the Notch pathway and the Hedgehog pathway. In addition, signaling molecules associated with these signaling pathways have been shown to be potential novel tumor markers for HB. Preoperative chemotherapy is the current standard of care for HB. Highly sensitive and specific tumor markers are not only important for the accurate diagnosis of HB but are also essential for predicting its clinical behaviors and prognosis. This review summarizes the recent advances in the molecular aspects of HB with a focus on the pathogenic signaling pathways and tumor markers. Their implications for diagnostics and prognostics are also discussed from a pathologist’s point of view.
References
Litten JB, Tomlinson GE. Liver tumors in children. Oncologist. 2008;13(7):812-820.
Finegold MJ, Egler RA, Goss JA, et al. Liver tumors: pediatric population. Liver Transpl. 2008;14(11):1545-1556.
Darbari A, Sabin KM, Shapiro CN, Schwarz KB. Epidemiology of primary hepatic malignancies in U.S. children. Hepatology. 2003;38(3):560-566.
Ishak KG, Glunz PR. Hepatoblastoma and hepatocarcinoma in infancy and childhood. Report of 47 cases. Cancer. 1967;20(3):396-422.
Stocker JT. Semin Diagn Pathol. Hepatoblastoma. 1994;11(2):136-143.
Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med. 1997;336(26):1855-1859.
Lingala S, Cui YY, Chen X, et al. Immunohistochemical staining of cancer stem cell markers in hepatocellular carcinoma. Exp Mol Pathol. 2010;89(1):27-35.
Adesina AM, Lopez-Terrada D, Wong KK, et al. Gene expression profiling reveals signatures characterizing histologic subtypes of hepatoblastoma and global deregulation in cell growth and survival pathways. Hum Pathol. 2009;40(6):843-853.
Hartmann W, Küchler J, Koch A, et al. Activation of phosphatidylinositol-3'-kinase/AKT signaling is essential in hepatoblastoma survival. Clin Cancer Res. 2009;15(14):4538-4545.
Tomizawa M, Saisho H. Signaling pathway of insulin-like growth factor-II as a target of molecular therapy for hepatoblastoma. World J Gastroenterol. 2006;12(40):6531-6535.
Wu CH, Nusse R. Ligand receptor interactions in the Wnt signaling pathway in Drosophila. J Biol Chem. 2002;277(44):41762-41769.
Nusse R. Wnt signaling and stem cell control. Cell Res. 2008;18(5):523-527.
Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta. 2003;1653(1):1-24
Buendia MA. Genetic alterations in hepatoblastoma and hepatocellular carcinoma: common and distinctive aspects. Med Pediatr Oncol. 2002;39(5):530-535.
Miller JR, Hocking AM, Brown JD, Moon RT. Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene. 1999;18(55):7860-7872.
Papkoff J, Rubinfeld B, Schryver B, Polakis P. Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes. Mol Cell Biol. 1996;16(5):2128-2134.
Behrens J, Jerchow BA, Würtele M, et al. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science. 1998;280(5363):596-599.
Lepourcelet M, Chen YN, France DS, et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell. 2004;5(1):91-102.
Jamieson C, Sharma M, Henderson BR. Wnt signaling from membrane to nucleus: β-catenin caught in a loop. Int J Biochem Cell Biol. 2012;44(6):847-850.
Tan X, Apte U, Micsenyi A,et al. Epidermal growth factor receptor: a novel target of the Wnt/beta-catenin pathway in liver. Gastroenterology. 2005;129(1):285-302.
Cairo S, Armengol C, Buendia MA. Activation of Wnt and Myc signaling in hepatoblastoma. Front Biosci (Elite Ed). 2012;4:480-486.
Orford K, Crockett C, Jensen JP, Weissman AM, Byers SW. Serine phosphorylation-regulated ubiquitination and degradation of beta-catenin. J Biol Chem. 1997;272(40):24735-24738.
Spiegelman VS, Slaga TJ, Pagano M, Minamoto T, Ronai Z, Fuchs SY. Wnt/beta-catenin signaling induces the expression and activity of betaTrCP ubiquitin ligase receptor. Mol Cell. 2000;5(5):877-882.
López-Terrada D, Gunaratne PH, Adesina AM, et al. Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors. Hum Pathol. 2009;40(6):783-794.
Wei Y, Fabre M, Branchereau S, Gauthier F, Perilongo G, Buendia MA. Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas. Oncogene. 2000;19(4):498-504.
Park WS, Oh RR, Park JY, et al. Nuclear localization of beta-catenin is an important prognostic factor in hepatoblastoma. J Pathol. 2001;193(4):483-490.
Oda H, Imai Y, Nakatsuru Y, Hata J, Ishikawa T. Somatic mutations of the APC gene in sporadic hepatoblastomas. Cancer Res. 1996;56(14):3320-3323.
Krawczuk-Rybak M, Jakubiuk-Tomaszuk A, Skiba E, Plawski A. Hepatoblastoma as a result of APC gene mutation. J Pediatr Gastroenterol Nutr. 2012;55(3):334-336.
Koch A, Weber N, Waha A, et al. Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas. J Pathol. 2004;204(5):546-554.
Taniguchi K, Roberts LR, Aderca IN, et al. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene. 2002;21(31):4863-4871.
Ueda Y, Hiyama E, Kamimatsuse A, Kamei N, Ogura K, Sueda T. Wnt signaling and telomerase activation of hepatoblastoma: correlation with chemosensitivity and surgical resectability. J Pediatr Surg. 2011;46(12):2221-2227.
Armengol C, Cairo S, Fabre M, Buendia MA. Wnt signaling and hepatocarcinogenesis: the hepatoblastoma model. Int J Biochem Cell Biol. 2011;43(2):265-270.
Kokolus K, Nemeth MJ. Non-canonical Wnt signaling pathways in hematopoiesis. Immunol Res. 2010;46(1-3):155-164.
von Schweinitz D, Fuchs J, Glüer S, Pietsch T. The occurrence of liver growth factor in hepatoblastoma. Eur J Pediatr Surg. 1998;8(3):133-136.
von Schweinitz D, Faundez A, Teichmann B, et al. Hepatocyte growth-factor-scatter factor can stimulate post-operative tumor-cell proliferation in childhood hepatoblastoma. Int J Cancer. 2000;85(2):151-159.
Purcell R, Childs M, Maibach R, et al. HGF/c-Met related activation of β-catenin in hepatoblastoma. J Exp Clin Cancer Res. 2011;30:96.
Ranganathan S, Tan X, Monga SP. beta-Catenin and met deregulation in childhood Hepatoblastomas. Pediatr Dev Pathol. 2005;8(4):435-447.
Zeng G, Apte U, Micsenyi A, Bell A, Monga SP. Tyrosine residues 654 and 670 in beta-catenin are crucial in regulation of Met-beta-catenin interactions. Exp Cell Res. 2006;312(18):3620-3630.
Monga SP, Mars WM, Pediaditakis P, et al. Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes. Cancer Res. 2002;62(7):2064-2071.
Grotegut S, Kappler R, Tarimoradi S, Lehembre F, Christofori G, Von Schweinitz D. Hepatocyte growth factor protects hepatoblastoma cells from chemotherapy-induced apoptosis by AKT activation. Int J Oncol. 2010;36(5):1261-1267.
Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284(5415):770-776.
Androutsellis-Theotokis A, Leker RR, Soldner F, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature. 2006;442(7104):823-826.
Tanimizu N, Miyajima A. Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors. J Cell Sci. 2004; 117(Pt 15):3165-3174.
Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7(9):678-689.
De Strooper B, Annaert W, Cupers P, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999;398(6727):518-522.
Davis RL, Turner DL. Vertebrate hairy and Enhancer of split related proteins: transcriptional repressors regulating cellular differentiation and embryonic patterning. Oncogene. 2001;20(58):8342-8357.
Litten JB, Chen TT, Schultz R, et al. Activated NOTCH2 is overexpressed in hepatoblastomas: an immunohistochemical study. Pediatr Dev Pathol. 2011;14(5):378-383.
Aktaş S, Zadeoğlulari Z, Erçetin P, Olgun N. The effect of differentiating and apoptotic agents on notch signalling pathway in hepatoblastoma. Hepatogastroenterology. 2010;57(101):891-898.
Weng AP, Aster JC. Multiple niches for Notch in cancer: context is everything. Curr Opin Genet Dev. 2004;14(1):48-54.
Chappell WH, Green TD, Spengeman JD, McCubrey JA, Akula SM, Bertrand FE. Increased protein expression of the PTEN tumor suppressor in the presence of constitutively active Notch-1. Cell Cycle. 2005;4(10):1389-1395.
Wang C, Qi R, Li N, et al. Notch1 signaling sensitizes tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human hepatocellular carcinoma cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. J Biol Chem. 2009;284(24):16183-16190.
McMahon AP, Ingham PW, Tabin CJ. Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol. 2003;53:1-114.
Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15(23):3059-3087.
Lum L, Beachy PA. The Hedgehog response network: sensors, switches, and routers. Science. 2004;304(5678):1755-1759.
Alcedo J, Noll M. Hedgehog and its patched-smoothened receptor complex: a novel signalling mechanism at the cell surface. Biol Chem. 1997;378(7):583-590.
Koebernick K, Pieler T. Gli-type zinc finger proteins as bipotential transducers of Hedgehog signaling. Differentiation. 2002;70(2-3):69-76.
Aza-Blanc P, Kornberg TB. Ci: a complex transducer of the hedgehog signal. Trends Genet. 1999;15(11):458-462.
Wang B, Fallon JF, Beachy PA. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell. 2000;100(4):423-434.
Sicklick JK, Li YX, Jayaraman A, et al. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis. 2006;27(4):748-757.
Eichenmüller M, Gruner I, Hagl B, et al. Blocking the hedgehog pathway inhibits hepatoblastoma growth. Hepatology. 2009;49(2):482-490.
Oue T, Yoneda A, Uehara S, Yamanaka H, Fukuzawa M. Increased expression of the hedgehog signaling pathway in pediatric solid malignancies. J Pediatr Surg. 2010;45(2):387-392.
Perilongo G, Shafford E, Plaschkes J; Liver Tumour Study Group of the International Society of Paediatric Oncology. SIOPEL trials using preoperative chemotherapy in hepatoblastoma. Lancet Oncol. 2000;1:94-100.
Zsíros J, Maibach R, Shafford E, et al. Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study. J Clin Oncol. 2010;28(15):2584-2590.
von Schweinitz D, Hecker H, Schmidt-von-Arndt G, Harms D. Prognostic factors and staging systems in childhood hepatoblastoma. Int J Cancer. 1997;74(6):593-599.
Brown J, Perilongo G, Shafford E, et al. Pretreatment prognostic factors for children with hepatoblastoma-- results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1. Eur J Cancer. 2000;36(11):1418-1425.
Morita K, Okabe I, Uchino J, et al. The proposed Japanese TNM classification of primary liver carcinoma in infants and children. Jpn J Clin Oncol. 1983;13(2):361-369.
Ortega JA, Krailo MD, Haas JE, et al. Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group. J Clin Oncol. 1991;9(12):2167-2176.
Douglass EC, Reynolds M, Finegold M, Cantor AB, Glicksman A. Cisplatin, vincristine, and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol. 1993;11(1):96-99.
Meyers RL, Rowland JR, Krailo M, Chen Z, Katzenstein HM, Malogolowkin MH. Predictive power of pretreatment prognostic factors in children with hepatoblastoma: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2009;53(6):1016-1022.
López-Terrada D, Zimmermann A. Current issues and controversies in the classification of pediatric hepatocellular tumors. Pediatr Blood Cancer. 2012;59(5):780-784.
Hirohashi S, Shimosato Y, Ino Y, Kishi K, Ohkura H, Mukojima T. Distribution of alpha-fetoprotein and immunoreactive carcinoembryonic antigen in human hepatocellular carcinoma and hepatoblastoma. Jpn J Clin Oncol. 1983;13(1):37-43.
Fasano M, Theise ND, Nalesnik M, et al. Immunohistochemical evaluation of hepatoblastomas with use of the hepatocyte-specific marker, hepatocyte paraffin 1, and the polyclonal anti-carcinoembryonic antigen. Mod Pathol. 1998;11(10):934-938.
De Ioris M, Brugieres L, Zimmermann A, et al. Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience. Eur J Cancer. 2008;44(4):545-550.
De Ioris M, Brugieres L, Zimmermann A, et al. Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience. Eur J Cancer. 2008;44(4):545-550.
Fukuzawa H, Urushihara N, Fukumoto K, et al. Can we predict the prognosis of resectable hepatoblastoma from serum alpha-fetoprotein response during preoperative chemotherapy? Pediatr Surg Int. 2012;28(9):887-891.
Zynger DL, Gupta A, Luan C, Chou PM, Yang GY, Yang XJ. Expression of glypican 3 in hepatoblastoma: an immunohistochemical study of 65 cases. Hum Pathol. 2008;39(2):224-230.
Ramsay AD, Bates AW, Williams S, Sebire NJ. Variable antigen expression in hepatoblastomas. Appl Immunohistochem Mol Morphol. 2008;16(2):140-147.
Inagawa S, Itabashi M, Adachi S, et al. Expression and prognostic roles of beta-catenin in hepatocellular carcinoma: correlation with tumor progression and postoperative survival. Clin Cancer Res. 2002;8(2):450-456.
Joo M, Lee HK, Kang YK. Expression of beta-catenin in hepatocellular carcinoma in relation to tumor cell proliferation and cyclin D1 expression. J Korean Med Sci. 2003;18(2):211-217.
Gupta K, Rane S, Das A, Marwaha RK, Menon P, Rao K. Relationship of β-Catenin and Postchemotherapy Histopathologic Changes With Overall Survival in Patients With Hepatoblastoma. J Pediatr Hematol Oncol. 2012 Jun 25. [Epub ahead of print]
Takayasu H, Horie H, Hiyama E, et al. Frequent deletions and mutations of the beta-catenin gene are associated with overexpression of cyclin D1 and fibronectin and poorly differentiated histology in childhood hepatoblastoma. Clin Cancer Res. 2001;7(4):901-908.
Koch A, Waha A, Hartmann W, et al. Elevated expression of Wnt antagonists is a common event in hepatoblastomas. Clin Cancer Res. 2005;11(12):4295-4304.
Purcell R, Childs M, Maibach R, et al. Potential biomarkers for hepatoblastoma: Results from the SIOPEL-3 study. Eur J Cancer. 2012;48(12):1853-1859.
Cairo S, Armengol C, De Reyniès A, et al. Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell. 2008;14(6):471-484.
Dezso K, Halász J, Bisgaard HC, et al. Delta-like protein (DLK) is a novel immunohistochemical marker for human hepatoblastomas. Virchows Arch. 2008;452(4):443-448.
Gao J, Song Z, Chen Y, et al. Deregulated expression of Notch receptors in human hepatocellular carcinoma. Dig Liver Dis. 2008; 40(2):114-121.
Li YC, Deng YH, Guo ZH, et al. Prognostic value of hedgehog signal component expressions in hepatoblastoma patients. J Med Res. 2010; 15(11):468-474.
Yamada S, Ohira M, Horie H, et al. Expression profiling and differential screening between hepatoblastomas and the corresponding normal livers: identification of high expression of the PLK1 oncogene as a poor-prognostic indicator of hepatoblastomas. Oncogene. 2004;23(35):5901-5911.
Tsukada M, Wakai T, Matsuda Y, et al. Loss of carcinoembryonic antigen-related cell adhesion molecule 1 expression predicts metachronous pulmonary metastasis and poor survival in patients with hepatoblastoma. J Pediatr Surg. 2009;44(8):1522-1528.
Honda S, Haruta M, Sugawara W, et al. The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients. Int J Cancer. 2008;123(5):1117-1125.
Sugawara W, Haruta M, Sasaki F, et al. Promoter hypermethylation of the RASSF1A gene predicts the poor outcome of patients with hepatoblastoma. Pediatr Blood Cancer. 2007;49(3):240-249
Sakamoto LH, DE Camargo B, Cajaiba M, Soares FA, Vettore AL. MT1G hypermethylation: a potential prognostic marker for hepatoblastoma. Pediatr Res. 2010;67(4):387-393.
Finegold MJ, Egler RA, Goss JA, et al. Liver tumors: pediatric population. Liver Transpl. 2008;14(11):1545-1556.
Darbari A, Sabin KM, Shapiro CN, Schwarz KB. Epidemiology of primary hepatic malignancies in U.S. children. Hepatology. 2003;38(3):560-566.
Ishak KG, Glunz PR. Hepatoblastoma and hepatocarcinoma in infancy and childhood. Report of 47 cases. Cancer. 1967;20(3):396-422.
Stocker JT. Semin Diagn Pathol. Hepatoblastoma. 1994;11(2):136-143.
Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med. 1997;336(26):1855-1859.
Lingala S, Cui YY, Chen X, et al. Immunohistochemical staining of cancer stem cell markers in hepatocellular carcinoma. Exp Mol Pathol. 2010;89(1):27-35.
Adesina AM, Lopez-Terrada D, Wong KK, et al. Gene expression profiling reveals signatures characterizing histologic subtypes of hepatoblastoma and global deregulation in cell growth and survival pathways. Hum Pathol. 2009;40(6):843-853.
Hartmann W, Küchler J, Koch A, et al. Activation of phosphatidylinositol-3'-kinase/AKT signaling is essential in hepatoblastoma survival. Clin Cancer Res. 2009;15(14):4538-4545.
Tomizawa M, Saisho H. Signaling pathway of insulin-like growth factor-II as a target of molecular therapy for hepatoblastoma. World J Gastroenterol. 2006;12(40):6531-6535.
Wu CH, Nusse R. Ligand receptor interactions in the Wnt signaling pathway in Drosophila. J Biol Chem. 2002;277(44):41762-41769.
Nusse R. Wnt signaling and stem cell control. Cell Res. 2008;18(5):523-527.
Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta. 2003;1653(1):1-24
Buendia MA. Genetic alterations in hepatoblastoma and hepatocellular carcinoma: common and distinctive aspects. Med Pediatr Oncol. 2002;39(5):530-535.
Miller JR, Hocking AM, Brown JD, Moon RT. Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene. 1999;18(55):7860-7872.
Papkoff J, Rubinfeld B, Schryver B, Polakis P. Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes. Mol Cell Biol. 1996;16(5):2128-2134.
Behrens J, Jerchow BA, Würtele M, et al. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science. 1998;280(5363):596-599.
Lepourcelet M, Chen YN, France DS, et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell. 2004;5(1):91-102.
Jamieson C, Sharma M, Henderson BR. Wnt signaling from membrane to nucleus: β-catenin caught in a loop. Int J Biochem Cell Biol. 2012;44(6):847-850.
Tan X, Apte U, Micsenyi A,et al. Epidermal growth factor receptor: a novel target of the Wnt/beta-catenin pathway in liver. Gastroenterology. 2005;129(1):285-302.
Cairo S, Armengol C, Buendia MA. Activation of Wnt and Myc signaling in hepatoblastoma. Front Biosci (Elite Ed). 2012;4:480-486.
Orford K, Crockett C, Jensen JP, Weissman AM, Byers SW. Serine phosphorylation-regulated ubiquitination and degradation of beta-catenin. J Biol Chem. 1997;272(40):24735-24738.
Spiegelman VS, Slaga TJ, Pagano M, Minamoto T, Ronai Z, Fuchs SY. Wnt/beta-catenin signaling induces the expression and activity of betaTrCP ubiquitin ligase receptor. Mol Cell. 2000;5(5):877-882.
López-Terrada D, Gunaratne PH, Adesina AM, et al. Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors. Hum Pathol. 2009;40(6):783-794.
Wei Y, Fabre M, Branchereau S, Gauthier F, Perilongo G, Buendia MA. Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas. Oncogene. 2000;19(4):498-504.
Park WS, Oh RR, Park JY, et al. Nuclear localization of beta-catenin is an important prognostic factor in hepatoblastoma. J Pathol. 2001;193(4):483-490.
Oda H, Imai Y, Nakatsuru Y, Hata J, Ishikawa T. Somatic mutations of the APC gene in sporadic hepatoblastomas. Cancer Res. 1996;56(14):3320-3323.
Krawczuk-Rybak M, Jakubiuk-Tomaszuk A, Skiba E, Plawski A. Hepatoblastoma as a result of APC gene mutation. J Pediatr Gastroenterol Nutr. 2012;55(3):334-336.
Koch A, Weber N, Waha A, et al. Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas. J Pathol. 2004;204(5):546-554.
Taniguchi K, Roberts LR, Aderca IN, et al. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene. 2002;21(31):4863-4871.
Ueda Y, Hiyama E, Kamimatsuse A, Kamei N, Ogura K, Sueda T. Wnt signaling and telomerase activation of hepatoblastoma: correlation with chemosensitivity and surgical resectability. J Pediatr Surg. 2011;46(12):2221-2227.
Armengol C, Cairo S, Fabre M, Buendia MA. Wnt signaling and hepatocarcinogenesis: the hepatoblastoma model. Int J Biochem Cell Biol. 2011;43(2):265-270.
Kokolus K, Nemeth MJ. Non-canonical Wnt signaling pathways in hematopoiesis. Immunol Res. 2010;46(1-3):155-164.
von Schweinitz D, Fuchs J, Glüer S, Pietsch T. The occurrence of liver growth factor in hepatoblastoma. Eur J Pediatr Surg. 1998;8(3):133-136.
von Schweinitz D, Faundez A, Teichmann B, et al. Hepatocyte growth-factor-scatter factor can stimulate post-operative tumor-cell proliferation in childhood hepatoblastoma. Int J Cancer. 2000;85(2):151-159.
Purcell R, Childs M, Maibach R, et al. HGF/c-Met related activation of β-catenin in hepatoblastoma. J Exp Clin Cancer Res. 2011;30:96.
Ranganathan S, Tan X, Monga SP. beta-Catenin and met deregulation in childhood Hepatoblastomas. Pediatr Dev Pathol. 2005;8(4):435-447.
Zeng G, Apte U, Micsenyi A, Bell A, Monga SP. Tyrosine residues 654 and 670 in beta-catenin are crucial in regulation of Met-beta-catenin interactions. Exp Cell Res. 2006;312(18):3620-3630.
Monga SP, Mars WM, Pediaditakis P, et al. Hepatocyte growth factor induces Wnt-independent nuclear translocation of beta-catenin after Met-beta-catenin dissociation in hepatocytes. Cancer Res. 2002;62(7):2064-2071.
Grotegut S, Kappler R, Tarimoradi S, Lehembre F, Christofori G, Von Schweinitz D. Hepatocyte growth factor protects hepatoblastoma cells from chemotherapy-induced apoptosis by AKT activation. Int J Oncol. 2010;36(5):1261-1267.
Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284(5415):770-776.
Androutsellis-Theotokis A, Leker RR, Soldner F, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature. 2006;442(7104):823-826.
Tanimizu N, Miyajima A. Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors. J Cell Sci. 2004; 117(Pt 15):3165-3174.
Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7(9):678-689.
De Strooper B, Annaert W, Cupers P, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999;398(6727):518-522.
Davis RL, Turner DL. Vertebrate hairy and Enhancer of split related proteins: transcriptional repressors regulating cellular differentiation and embryonic patterning. Oncogene. 2001;20(58):8342-8357.
Litten JB, Chen TT, Schultz R, et al. Activated NOTCH2 is overexpressed in hepatoblastomas: an immunohistochemical study. Pediatr Dev Pathol. 2011;14(5):378-383.
Aktaş S, Zadeoğlulari Z, Erçetin P, Olgun N. The effect of differentiating and apoptotic agents on notch signalling pathway in hepatoblastoma. Hepatogastroenterology. 2010;57(101):891-898.
Weng AP, Aster JC. Multiple niches for Notch in cancer: context is everything. Curr Opin Genet Dev. 2004;14(1):48-54.
Chappell WH, Green TD, Spengeman JD, McCubrey JA, Akula SM, Bertrand FE. Increased protein expression of the PTEN tumor suppressor in the presence of constitutively active Notch-1. Cell Cycle. 2005;4(10):1389-1395.
Wang C, Qi R, Li N, et al. Notch1 signaling sensitizes tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human hepatocellular carcinoma cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. J Biol Chem. 2009;284(24):16183-16190.
McMahon AP, Ingham PW, Tabin CJ. Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol. 2003;53:1-114.
Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15(23):3059-3087.
Lum L, Beachy PA. The Hedgehog response network: sensors, switches, and routers. Science. 2004;304(5678):1755-1759.
Alcedo J, Noll M. Hedgehog and its patched-smoothened receptor complex: a novel signalling mechanism at the cell surface. Biol Chem. 1997;378(7):583-590.
Koebernick K, Pieler T. Gli-type zinc finger proteins as bipotential transducers of Hedgehog signaling. Differentiation. 2002;70(2-3):69-76.
Aza-Blanc P, Kornberg TB. Ci: a complex transducer of the hedgehog signal. Trends Genet. 1999;15(11):458-462.
Wang B, Fallon JF, Beachy PA. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell. 2000;100(4):423-434.
Sicklick JK, Li YX, Jayaraman A, et al. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis. 2006;27(4):748-757.
Eichenmüller M, Gruner I, Hagl B, et al. Blocking the hedgehog pathway inhibits hepatoblastoma growth. Hepatology. 2009;49(2):482-490.
Oue T, Yoneda A, Uehara S, Yamanaka H, Fukuzawa M. Increased expression of the hedgehog signaling pathway in pediatric solid malignancies. J Pediatr Surg. 2010;45(2):387-392.
Perilongo G, Shafford E, Plaschkes J; Liver Tumour Study Group of the International Society of Paediatric Oncology. SIOPEL trials using preoperative chemotherapy in hepatoblastoma. Lancet Oncol. 2000;1:94-100.
Zsíros J, Maibach R, Shafford E, et al. Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study. J Clin Oncol. 2010;28(15):2584-2590.
von Schweinitz D, Hecker H, Schmidt-von-Arndt G, Harms D. Prognostic factors and staging systems in childhood hepatoblastoma. Int J Cancer. 1997;74(6):593-599.
Brown J, Perilongo G, Shafford E, et al. Pretreatment prognostic factors for children with hepatoblastoma-- results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1. Eur J Cancer. 2000;36(11):1418-1425.
Morita K, Okabe I, Uchino J, et al. The proposed Japanese TNM classification of primary liver carcinoma in infants and children. Jpn J Clin Oncol. 1983;13(2):361-369.
Ortega JA, Krailo MD, Haas JE, et al. Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group. J Clin Oncol. 1991;9(12):2167-2176.
Douglass EC, Reynolds M, Finegold M, Cantor AB, Glicksman A. Cisplatin, vincristine, and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol. 1993;11(1):96-99.
Meyers RL, Rowland JR, Krailo M, Chen Z, Katzenstein HM, Malogolowkin MH. Predictive power of pretreatment prognostic factors in children with hepatoblastoma: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2009;53(6):1016-1022.
López-Terrada D, Zimmermann A. Current issues and controversies in the classification of pediatric hepatocellular tumors. Pediatr Blood Cancer. 2012;59(5):780-784.
Hirohashi S, Shimosato Y, Ino Y, Kishi K, Ohkura H, Mukojima T. Distribution of alpha-fetoprotein and immunoreactive carcinoembryonic antigen in human hepatocellular carcinoma and hepatoblastoma. Jpn J Clin Oncol. 1983;13(1):37-43.
Fasano M, Theise ND, Nalesnik M, et al. Immunohistochemical evaluation of hepatoblastomas with use of the hepatocyte-specific marker, hepatocyte paraffin 1, and the polyclonal anti-carcinoembryonic antigen. Mod Pathol. 1998;11(10):934-938.
De Ioris M, Brugieres L, Zimmermann A, et al. Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience. Eur J Cancer. 2008;44(4):545-550.
De Ioris M, Brugieres L, Zimmermann A, et al. Hepatoblastoma with a low serum alpha-fetoprotein level at diagnosis: the SIOPEL group experience. Eur J Cancer. 2008;44(4):545-550.
Fukuzawa H, Urushihara N, Fukumoto K, et al. Can we predict the prognosis of resectable hepatoblastoma from serum alpha-fetoprotein response during preoperative chemotherapy? Pediatr Surg Int. 2012;28(9):887-891.
Zynger DL, Gupta A, Luan C, Chou PM, Yang GY, Yang XJ. Expression of glypican 3 in hepatoblastoma: an immunohistochemical study of 65 cases. Hum Pathol. 2008;39(2):224-230.
Ramsay AD, Bates AW, Williams S, Sebire NJ. Variable antigen expression in hepatoblastomas. Appl Immunohistochem Mol Morphol. 2008;16(2):140-147.
Inagawa S, Itabashi M, Adachi S, et al. Expression and prognostic roles of beta-catenin in hepatocellular carcinoma: correlation with tumor progression and postoperative survival. Clin Cancer Res. 2002;8(2):450-456.
Joo M, Lee HK, Kang YK. Expression of beta-catenin in hepatocellular carcinoma in relation to tumor cell proliferation and cyclin D1 expression. J Korean Med Sci. 2003;18(2):211-217.
Gupta K, Rane S, Das A, Marwaha RK, Menon P, Rao K. Relationship of β-Catenin and Postchemotherapy Histopathologic Changes With Overall Survival in Patients With Hepatoblastoma. J Pediatr Hematol Oncol. 2012 Jun 25. [Epub ahead of print]
Takayasu H, Horie H, Hiyama E, et al. Frequent deletions and mutations of the beta-catenin gene are associated with overexpression of cyclin D1 and fibronectin and poorly differentiated histology in childhood hepatoblastoma. Clin Cancer Res. 2001;7(4):901-908.
Koch A, Waha A, Hartmann W, et al. Elevated expression of Wnt antagonists is a common event in hepatoblastomas. Clin Cancer Res. 2005;11(12):4295-4304.
Purcell R, Childs M, Maibach R, et al. Potential biomarkers for hepatoblastoma: Results from the SIOPEL-3 study. Eur J Cancer. 2012;48(12):1853-1859.
Cairo S, Armengol C, De Reyniès A, et al. Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell. 2008;14(6):471-484.
Dezso K, Halász J, Bisgaard HC, et al. Delta-like protein (DLK) is a novel immunohistochemical marker for human hepatoblastomas. Virchows Arch. 2008;452(4):443-448.
Gao J, Song Z, Chen Y, et al. Deregulated expression of Notch receptors in human hepatocellular carcinoma. Dig Liver Dis. 2008; 40(2):114-121.
Li YC, Deng YH, Guo ZH, et al. Prognostic value of hedgehog signal component expressions in hepatoblastoma patients. J Med Res. 2010; 15(11):468-474.
Yamada S, Ohira M, Horie H, et al. Expression profiling and differential screening between hepatoblastomas and the corresponding normal livers: identification of high expression of the PLK1 oncogene as a poor-prognostic indicator of hepatoblastomas. Oncogene. 2004;23(35):5901-5911.
Tsukada M, Wakai T, Matsuda Y, et al. Loss of carcinoembryonic antigen-related cell adhesion molecule 1 expression predicts metachronous pulmonary metastasis and poor survival in patients with hepatoblastoma. J Pediatr Surg. 2009;44(8):1522-1528.
Honda S, Haruta M, Sugawara W, et al. The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients. Int J Cancer. 2008;123(5):1117-1125.
Sugawara W, Haruta M, Sasaki F, et al. Promoter hypermethylation of the RASSF1A gene predicts the poor outcome of patients with hepatoblastoma. Pediatr Blood Cancer. 2007;49(3):240-249
Sakamoto LH, DE Camargo B, Cajaiba M, Soares FA, Vettore AL. MT1G hypermethylation: a potential prognostic marker for hepatoblastoma. Pediatr Res. 2010;67(4):387-393.
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2012-10-29
How to Cite
Chen, MD, PhD, W., Kozielski, MD, R., LeVea, MD, PhD, C., & Chen, MD, PhD, F. (2012). The Advances in Molecular Biology of Hepatoblastoma: Implications for Diagnostic Pathology. North American Journal of Medicine and Science, 5(4). Retrieved from https://najms.com/index.php/najms/article/view/214
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