Bridging molecular basis, prognosis, and treatment of pediatric liver tumors

Abstract

A deeper understanding of the genetic and molecular basis of hepatoblastoma (HB) has fueled the hope to help in identifying genes and signaling pathways that are amenable to therapeutic intervention. However, it has become clear that HB is a genetically very simple cancer and that rather alterations of the transcriptome or epigenome will facilitate a more stratified and rationalized approach to current therapeutics. In this review, we discuss recent findings on genomic, transcriptomic, and epigenomic data and their potential to serve as biomarkers and predictors of patient’s outcome. We also describe the state of the art in HB experimental biology, the in vitro and in vivo HB models that are currently available, and their use to improve our understanding of this disease and identify new treatment options.

Keywords

Hepatoblastoma / childhood liver cancer / genomics / transcriptomics / epigenomics / cell models / xenograft / therapeutic target

References

[1] Kehm RD,Poynter JN,Spector LG.Do pregnancy characteristics contribute to rising childhood cancer incidence rates in the United States?.Pediatr Blood Cancer2018;65 PMCID:PMC5766387

[2] Schmid I.Pediatric hepatocellular carcinoma: challenges and solutions.J Hepatocell Carcinoma2017;4:15-21 PMCID:PMC5248979

[3] Rikhi RR,Hoffman RI,Bateman M.Hepatoblastoma: a need for cell lines and tissue banks to develop targeted drug therapies.Front Pediatr2016;4:22 PMCID:PMC4800278

[4] Llovet JM,Villanueva A.Hepatocellular carcinoma.Nat Rev Dis Primers2021;7:6

[5] Czauderna P.Adult type vs. Childhood hepatocellular carcinoma--are they the same or different lesions?.Med Pediatr Oncol2002;39:519-23

[6] Czauderna P,Perilongo G.Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group.J Clin Oncol2002;20:2798-804

[7] Katzenstein HM,Malogolowkin MH.Hepatocellular carcinoma in children and adolescents: results from the Pediatric Oncology Group and the Children's Cancer Group intergroup study.J Clin Oncol2002;20:2789-97

[8] Lopez-Terrada D,de Davila MT.Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium.Mod Pathol2014;27:472-91

[9] Prokurat A,Kosciesza A,Kappeler A.Transitional liver cell tumors (TLCT) in older children and adolescents: a novel group of aggressive hepatic tumors expressing beta-catenin.Med Pediatr Oncol2002;39:510-8

[10] Zimmermann A.The emerging family of hepatoblastoma tumours: from ontogenesis to oncogenesis.Eur J Cancer2005;41:1503-14

[11] Cairo S,De Reynies A.Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer.Cancer Cell2008;14:471-84

[12] Koch A,Albrecht S,von Schweinitz D.Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene.Cancer Res1999;59:269-73

[13] Wei Y,Branchereau S,Perilongo G.Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas.Oncogene2000;19:498-504

[14] Eichenmüller M,Kreuder M.The genomic landscape of hepatoblastoma and their progenies with HCC-like features.J Hepatol2014;61:1312-20

[15] Sekiguchi M,Kawai T.Integrated multiomics analysis of hepatoblastoma unravels its heterogeneity and provides novel druggable targets.NPJ Precis Oncol2020;4:20 PMCID:PMC7341754

[16] Sumazin P,Trevino LR.Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups.Hepatology2017;65:104-21

[17] Hirschman BA,Tomlinson GE.The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds.J Pediatr2005;147:263-6

[18] Koch A,Waha A.Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas.J Pathol2004;204:546-54

[19] Taniguchi K,Aderca IN.Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas.Oncogene2002;21:4863-71

[20] Trobaugh-Lotrario AD,Feusner JH.Hepatoblastoma in children with Beckwith-Wiedemann syndrome: does it warrant different treatment?.J Pediatr Hematol Oncol2014;36:369-73

[21] Ansell P,Roman E,Birch JM.Relationships between perinatal and maternal characteristics and hepatoblastoma: a report from the UKCCS.Eur J Cancer2005;41:741-8

[22] McLaughlin CC,Schymura MJ,Zdeb MS.Maternal and infant birth characteristics and hepatoblastoma.Am J Epidemiol2006;163:818-28

[23] Grobner SN,Weischenfeldt J.The landscape of genomic alterations across childhood cancers.Nature2018;555:321-7

[24] Vokuhl C,Haberle B,Schneppenheim R.Small cell undifferentiated (SCUD) hepatoblastomas: all malignant rhabdoid tumors?.Genes Chromosomes Cancer2016;55:925-31

[25] Zhou S,Gupta S.Hepatocellular malignant neoplasm, NOS: a clinicopathological study of 11 cases from a single institution.Histopathology2017;71:813-22 PMCID:PMC7521842

[26] Cairo S,Maibach R.A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients.Eur J Cancer2020;141:30-9

[27] Carrillo-Reixach J,Simon-Coma M.Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications.J Hepatol2020;73:328-41

[28] Jeong Y,Stehr H.Role of KEAP1/NFE2L2 Mutations in the chemotherapeutic response of patients with non-small cell lung cancer.Clin Cancer Res2020;26:274-81 PMCID:PMC6942632

[29] Jia D,Jing Y.Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex.Hepatology2014;60:1686-96

[30] Lee H,Ainechi S.General paucity of genomic alteration and low tumor mutation burden in refractory and metastatic hepatoblastoma: comprehensive genomic profiling study.Hum Pathol2017;70:84-91

[31] Cairo S,de Reynies A.Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer.Proc Natl Acad Sci U S A2010;107:20471-6 PMCID:PMC2996672

[32] Hooks KB,Fazli H.New insights into diagnosis and therapeutic options for proliferative hepatoblastoma.Hepatology2018;68:89-102

[33] Cui X,Zheng S,Dong R.Genome-wide analysis of DNA methylation in hepatoblastoma tissues.Oncol Lett2016;12:1529-34 PMCID:PMC4950688

[34] Honda S,Suzuki H.Clinical prognostic value of DNA methylation in hepatoblastoma: four novel tumor suppressor candidates.Cancer Sci2016;107:812-9 PMCID:PMC4968605

[35] Maschietto M,Kashiwabara AY.DNA methylation landscape of hepatoblastomas reveals arrest at early stages of liver differentiation and cancer-related alterations.Oncotarget2017;8:97871-89 PMCID:PMC5716698

[36] Buj R,Diez-Villanueva A.Quantification of unmethylated Alu (QUAlu): a tool to assess global hypomethylation in routine clinical samples.Oncotarget2016;7:10536-46 PMCID:PMC4891138

[37] Meyers RL,Hiyama E.Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration.Lancet Oncol2017;18:122-31 PMCID:PMC5650231

[38] Doi I.Establishment of a cell line and its clonal sublines from a patient with hepatoblastoma.Gann1976;67:1-10

[39] Pietsch T,Albrecht S,Wolf HK.Characterization of the continuous cell line HepT1 derived from a human hepatoblastoma.Lab Invest1996;74:809-18

[40] Hartmann W,Koch A.p57(KIP2) is not mutated in hepatoblastoma but shows increased transcriptional activity in a comparative analysis of the three imprinted genes p57(KIP2), IGF2, and H19.Am J Pathol2000;157:1393-403 PMCID:PMC1850179

[41] Aden DP,Plotkin S,Knowles BB.Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line.Nature1979;282:615-6

[42] Lopez-Terrada D,Finegold MJ.Hep G2 is a hepatoblastoma-derived cell line.Hum Pathol2009;40:1512-5

[43] Knowles BB,Aden DP.Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis B surface antigen.Science1980;209:497-9

[44] Hartmann W,Koch A.Activation of phosphatidylinositol-3'-kinase/AKT signaling is essential in hepatoblastoma survival.Clin Cancer Res2009;15:4538-45

[45] Eriksson T,Gray SG.Methylation changes in the human IGF2 p3 promoter parallel IGF2 expression in the primary tumor, established cell line, and xenograft of a human hepatoblastoma.Exp Cell Res2001;270:88-95

[46] Seeliger H,Kleespies A,Bruns CJ.Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis.Cancer Metastasis Rev2007;26:611-21

[47] Guba M,Steinbauer M.Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor.Nat Med2002;8:128-35

[48] Wagner F,Lederer C.Rapamycin blocks hepatoblastoma growth in vitro and in vivo implicating new treatment options in high-risk patients.Eur J Cancer2012;48:2442-50

[49] Wan X,Shen N,Helman LJ.Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism.Oncogene2007;26:1932-40

[50] Nielsen D,Sornsakrin M,Nashan B.The use of everolimus in pediatric liver transplant recipients: first experience in a single center.Pediatr Transplant2011;15:510-4

[51] Eichenmüller M,Hagl B.Blocking the hedgehog pathway inhibits hepatoblastoma growth.Hepatology2009;49:482-90

[52] Huang S,Zhang X.Activation of the hedgehog pathway in human hepatocellular carcinomas.Carcinogenesis2006;27:1334-40

[53] Cory S.Killing cancer cells by flipping the Bcl-2/Bax switch.Cancer Cell2005;8:5-6

[54] Lieber J,Eicher C.Inhibition of Bcl-2 and Bcl-X enhances chemotherapy sensitivity in hepatoblastoma cells.Pediatr Blood Cancer2010;55:1089-95

[55] Lieber J,Wenz J.The BH3 mimetic ABT-737 increases treatment efficiency of paclitaxel against hepatoblastoma.BMC Cancer2011;11:362 PMCID:PMC3176244

[56] Munoz M.The Neurokinin-1 receptor antagonist aprepitant: an intelligent bullet against cancer?.Cancers (Basel)2020;12:2682 PMCID:PMC7564414

[57] Berger M,Ilmer M.Hepatoblastoma cells express truncated neurokinin-1 receptor and can be growth inhibited by aprepitant in vitro and in vivo.J Hepatol2014;60:985-94

[58] Eberherr C,Vokuhl C.Targeting excessive MYCN expression using MLN8237 and JQ1 impairs the growth of hepatoblastoma cells.Int J Oncol2019;54:1853-63

[59] Wagner AE,Haberle B.SP8 promotes an aggressive phenotype in hepatoblastoma via FGF8 activation.Cancers (Basel)2020;12:2294 PMCID:PMC7465460

[60] Whitlock RS,Vasudevan SA.Animal modeling of pediatric liver cancer.Cancers (Basel)2020;12:273 PMCID:PMC7072332

[61] Mokkapati S,Huang L.beta-catenin activation in a novel liver progenitor cell type is sufficient to cause hepatocellular carcinoma and hepatoblastoma.Cancer Res2014;74:4515-25 PMCID:PMC4134699

[62] Bissig-Choisat B,Legras XD.Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer.J Hepatol2016;65:325-33 PMCID:PMC5668139

[63] Nicolle D,Simon-Coma M.Patient-derived mouse xenografts from pediatric liver cancer predict tumor recurrence and advise clinical management.Hepatology2016;64:1121-35

[64] Kats D,Berlow NE.Volasertib preclinical activity in high-risk hepatoblastoma.Oncotarget2019;10:6403-17 PMCID:PMC6849653

[65] Yamada S,Horie H.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.Oncogene2004;23:5901-11

[66] Eloranta K,Liljestrom E.Chloroquine triggers cell death and inhibits PARPs in cell models of aggressive hepatoblastoma.Front Oncol2020;10:1138 PMCID:PMC7379510

[67] Woodfield SE,Patel RH.MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma.Sci Rep2021;11:2967 PMCID:PMC7859402