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Jiao J, Saxena R, Morotti R. Hepatoblastoma: Comprehensive Review With Recent Updates. Adv Anat Pathol 2025:00125480-990000000-00143. [PMID: 40178831 DOI: 10.1097/pap.0000000000000495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
Hepatoblastoma (HB), the most common primary malignant liver tumor of childhood, demonstrates remarkable histologic heterogeneity and can be classified into epithelial or mixed epithelial-mesenchymal subtypes. This review summarizes updates in histologic classification, molecular signatures, staging, and risk stratification of HB. The Children's Hepatic tumors International Collaboration represents an international effort to standardize the study of rare pediatric liver tumors; emphasis continues to remain on improving risk stratification by a combination of clinical, histologic, and molecular features to tailor treatment in a bid to reduce toxicity while maintaining or improving efficacy. Pure fetal HB is cured by complete resection without the need for adjuvant chemotherapy. Malignant rhabdoid tumors have been parsed out from small cell undifferentiated HBs by negative INI-1 staining on immunohistochemistry; these tumors require a distinct and more aggressive chemotherapeutic regimen. The significance of recently characterized "blastema" component in HB remains to be elucidated. Hepatocellular neoplasm, not otherwise specified, is a provisional diagnostic category for tumors exhibiting either intermediate or a combination of both HB and hepatocellular carcinoma histologic features. The Children's Hepatic tumors International Collaboration risk stratification algorithm includes age as an important discriminator of risk, in addition to AFP, metastasis, and PreTreatment EXTent of disease stage and its annotations.
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Affiliation(s)
- Jingjing Jiao
- Department of Pathology, Yale School of Medicine, New Haven, CT
| | - Romil Saxena
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA
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Cagnin S, Pontisso P, Martini A. SerpinB3: A Multifaceted Player in Health and Disease-Review and Future Perspectives. Cancers (Basel) 2024; 16:2579. [PMID: 39061218 PMCID: PMC11274807 DOI: 10.3390/cancers16142579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/10/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
SerpinB3, a member of the serine-protease inhibitor family, has emerged as a crucial player in various physiological and pathological processes. Initially identified as an oncogenic factor in squamous cell carcinomas, SerpinB3's intricate involvement extends from fibrosis progression and cancer to cell protection in acute oxidative stress conditions. This review explores the multifaceted roles of SerpinB3, focusing on its implications in fibrosis, metabolic syndrome, carcinogenesis and immune system impairment. Furthermore, its involvement in tissue protection from oxidative stress and wound healing underscores its potential as diagnostic and therapeutic tool. Recent studies have described the therapeutic potential of targeting SerpinB3 through its upstream regulators, offering novel strategies for cancer treatment development. Overall, this review underscores the importance of further research to fully elucidate the mechanisms of action of SerpinB3 and to exploit its therapeutic potential across various medical conditions.
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Affiliation(s)
| | - Patrizia Pontisso
- Department of Medicine, University of Padova, 35123 Padova, Italy; (S.C.); (A.M.)
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Kato Y, Fukazawa T, Tanimoto K, Kanawa M, Kojima M, Saeki I, Kurihara S, Touge R, Hirohashi N, Okada S, Hiyama E. Achaete-scute family bHLH transcription factor 2 activation promotes hepatoblastoma progression. Cancer Sci 2024; 115:847-858. [PMID: 38183173 PMCID: PMC10921009 DOI: 10.1111/cas.16051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 11/16/2023] [Accepted: 12/08/2023] [Indexed: 01/07/2024] Open
Abstract
Achaete-scute family bHLH transcription factor 2 (ASCL2) is highly expressed in hepatoblastoma (HB) tissues, but its role remains unclear. Thus, biological changes in the HB cell line HepG2 in response to induced ASCL2 expression were assessed. ASCL2 expression was induced in HepG2 cells using the Tet-On 3G system, which includes doxycycline. Cell viability, proliferation activity, mobility, and stemness were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony-formation, migration, invasion, and sphere-formation assays. Quantitative reverse-transcription polymerase chain reaction was used to assess the expression of markers for proliferation (CCND1 and MYC), epithelial-mesenchymal transition (EMT; SNAI1, TWIST1, and ZEB1), mesenchymal-epithelial transition (CDH1), and stemness (KLF4, POU5F1, and SOX9). Compared with the non-induced HepG2 cells, cells with induced ASCL2 expression showed significant increases in viability, colony number, migration area (%), and sphere number on days 7, 14, 8, and 7, respectively, and invasion area (%) after 90 h. Furthermore, induction of ASCL2 expression significantly upregulated CCND1, MYC, POU5F1, SOX9, and KLF4 expression on days 2, 2, 3, 3, and 5, respectively, and increased the ratios of SNAI1, TWIST1, and ZEB1 to CDH1 on day 5. ASCL2 promoted the formation of malignant phenotypes in HepG2 cells, which may be correlated with the upregulation of the Wnt signaling pathway-, EMT-, and stemness-related genes. ASCL2 activation may therefore be involved in the progression of HB.
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Affiliation(s)
- Yutaka Kato
- Department of Pediatrics, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Takahiro Fukazawa
- Natural Science Center for Basic Research and DevelopmentHiroshima UniversityHiroshimaJapan
- Division of Medical Research Support, Advanced Research Support CenterEhime UniversityToonJapan
| | - Keiji Tanimoto
- Department of Radiation Disaster Medicine, Research Institute for Radiation Biology and MedicineHiroshima UniversityHiroshimaJapan
| | - Masami Kanawa
- Natural Science Center for Basic Research and DevelopmentHiroshima UniversityHiroshimaJapan
| | - Masato Kojima
- Natural Science Center for Basic Research and DevelopmentHiroshima UniversityHiroshimaJapan
- Department of Surgery, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
- Department of Pediatric SurgeryHiroshima University HospitalHiroshimaJapan
| | - Isamu Saeki
- Department of Surgery, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
- Department of Pediatric SurgeryHiroshima University HospitalHiroshimaJapan
| | - Sho Kurihara
- Department of Surgery, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
- Department of Pediatric SurgeryHiroshima University HospitalHiroshimaJapan
| | - Ryo Touge
- Department of Surgery, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
- Department of Pediatric SurgeryHiroshima University HospitalHiroshimaJapan
| | - Nobuyuki Hirohashi
- Department of Radiation Disaster Medicine, Research Institute for Radiation Biology and MedicineHiroshima UniversityHiroshimaJapan
| | - Satoshi Okada
- Department of Pediatrics, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Eiso Hiyama
- Natural Science Center for Basic Research and DevelopmentHiroshima UniversityHiroshimaJapan
- Department of Surgery, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
- Department of Pediatric SurgeryHiroshima University HospitalHiroshimaJapan
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Sumazin P, Peters TL, Sarabia SF, Kim HR, Urbicain M, Hollingsworth EF, Alvarez KR, Perez CR, Pozza A, Najaf Panah MJ, Epps JL, Scorsone K, Zorman B, Katzenstein H, O'Neill AF, Meyers R, Tiao G, Geller J, Ranganathan S, Rangaswami AA, Woodfield SE, Goss JA, Vasudevan SA, Heczey A, Roy A, Fisher KE, Alaggio R, Patel KR, Finegold MJ, López-Terrada DH. Hepatoblastomas with carcinoma features represent a biological spectrum of aggressive neoplasms in children and young adults. J Hepatol 2022; 77:1026-1037. [PMID: 35577029 PMCID: PMC9524481 DOI: 10.1016/j.jhep.2022.04.035] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 02/15/2022] [Accepted: 04/21/2022] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS. METHODS We tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8). RESULTS Molecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (∼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes. CONCLUSIONS Our study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms. LAY SUMMARY We molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.
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Affiliation(s)
- Pavel Sumazin
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA.
| | - Tricia L Peters
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA; Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Stephen F Sarabia
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA; Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Hyunjae R Kim
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Martin Urbicain
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA; Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Emporia Faith Hollingsworth
- Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Karla R Alvarez
- Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Cintia R Perez
- Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Alice Pozza
- Department of Pathology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Mohammad Javad Najaf Panah
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Jessica L Epps
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Kathy Scorsone
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Barry Zorman
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Howard Katzenstein
- Nemours Children's Specialty Care and Wolfson Children's Hospital, Jacksonville, FL, USA
| | - Allison F O'Neill
- Dana-Farber Cancer Institute and Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Department of Pediatric Oncology, Boston, MA, USA
| | | | - Greg Tiao
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Jim Geller
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | | | - Arun A Rangaswami
- Department of Pediatrics/Division of Hematology-Oncology, University of California San Francisco, San Francisco, CA, USA
| | - Sarah E Woodfield
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA; Department of Surgery, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - John A Goss
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA; Department of Abdominal Transplantation, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Sanjeev A Vasudevan
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA; Department of Surgery, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Andras Heczey
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Angshumoy Roy
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA; Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Kevin E Fisher
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA; Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Rita Alaggio
- Department of Pathology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Kalyani R Patel
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA; Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA
| | - Milton J Finegold
- Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA.
| | - Dolores H López-Terrada
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA; Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital and Cancer Center, Houston, TX, USA.
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Sergi CM, Rojas-Vasquez M, Noga M, Dicken B. 'Teratoid' Hepatoblastoma: An Intriguing Variant of Mixed Epithelial-Mesenchymal Hepatoblastoma. CHILDREN (BASEL, SWITZERLAND) 2022; 9:565. [PMID: 35455609 PMCID: PMC9024637 DOI: 10.3390/children9040565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/04/2022] [Accepted: 04/11/2022] [Indexed: 11/28/2022]
Abstract
Liver neoplasms are quite rare in childhood. They often involve 6.7 cases per 10 million children aged 18 years or younger. Hepatoblastoma (HB) is the most frequent tumor, but this neoplasm's rarity points essentially to the difficulty of performing biologic studies and large-scale therapeutic trials. On the pathological ground, HB is separated into an entirely epithelial neoplasm or a mixed neoplasm with epithelial and mesenchymal components. This last category has been further subdivided into harboring teratoid features or not. The 'teratoid' HB includes a mixture of components with heterologous origin. The heterologous components include neuroectoderm, endoderm, or melanin-holding cells with or without mesenchymal components. The most important criterium for the teratoid component is neuroepithelium, melanin, and, more recently, a yolk-sac-like component and neuroendocrine components. The mesenchymal components include muscle, osteoid, and cartilage, which are most often observed mainly in 'teratoid' neoplasms. The teratoid component or mesenchymal components are diagnosed with biopsies. They appear more prominent after chemotherapy due to the response and shrinkage of epithelial elements and non- or low-responsive components of mixed HB. This review focuses on the clinical, radiological, and pathological findings of HB with teratoid features.
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Affiliation(s)
- Consolato M. Sergi
- Anatomic Pathology Division, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
- Department of Lab. Medicine and Pathology, Stollery Children’s Hospital, University of Alberta, Edmonton, AB T6G 2B7, Canada
| | - Marta Rojas-Vasquez
- Department of Pediatric Hematology-Oncology, Stollery Children’s Hospital, University of Alberta, Edmonton, AB T6G 2B7, Canada;
| | - Michelle Noga
- Department of Pediatric Radiology, Stollery Children’s Hospital, University of Alberta, Edmonton, AB T6G 2B7, Canada;
| | - Bryan Dicken
- Department of Surgery, Stollery Children’s Hospital, University of Alberta, Edmonton, AB T6G 2B7, Canada;
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Schmidt A, Armento A, Bussolati O, Chiu M, Ellerkamp V, Scharpf MO, Sander P, Schmid E, Warmann SW, Fuchs J. Hepatoblastoma: glutamine depletion hinders cell viability in the embryonal subtype but high GLUL expression is associated with better overall survival. J Cancer Res Clin Oncol 2021; 147:3169-3181. [PMID: 34235580 PMCID: PMC8484192 DOI: 10.1007/s00432-021-03713-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 06/24/2021] [Indexed: 11/26/2022]
Abstract
Purpose Glutamine plays an important role in cell viability and growth of various tumors. For the fetal subtype of hepatoblastoma, growth inhibition through glutamine depletion was shown. We studied glutamine depletion in embryonal cell lines of hepatoblastoma carrying different mutations. Since asparagine synthetase was identified as a prognostic factor and potential therapeutic target in adult hepatocellular carcinoma, we investigated the expression of its gene ASNS and of the gene GLUL, encoding for glutamine synthetase, in hepatoblastoma specimens and cell lines and investigated the correlation with overall survival. Methods We correlated GLUL and ASNS expression with overall survival using publicly available microarray and clinical data. We examined GLUL and ASNS expression by RT-qPCR and by Western blot analysis in the embryonal cell lines Huh-6 and HepT1, and in five hepatoblastoma specimens. In the same cell lines, we investigated the effects of glutamine depletion. Hepatoblastoma biopsies were examined for histology and CTNNB1 mutations. Results High GLUL expression was associated with a higher median survival time. Independent of mutations and histology, hepatoblastoma samples showed strong GLUL expression and glutamine synthesis. Glutamine depletion resulted in the inhibition of proliferation and of cell viability in both embryonal hepatoblastoma cell lines. ASNS expression did not correlate with overall survival. Conclusion Growth inhibition resulting from glutamine depletion, as described for the hepatoblastoma fetal subtype, is also detected in established embryonal hepatoblastoma cell lines carrying different mutations. At variance with adult hepatocellular carcinoma, in hepatoblastoma asparagine synthetase has no prognostic significance.
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Affiliation(s)
- Andreas Schmidt
- Department of Paediatric Surgery and Paediatric Urology, University Children's Hospital, Eberhard Karls University Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany.
| | - Angela Armento
- Department of Paediatric Surgery and Paediatric Urology, University Children's Hospital, Eberhard Karls University Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany
- Department for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Elfriede-Aulhorn-Straße 7, 72076, Tuebingen, Germany
| | - Ovidio Bussolati
- Department of Medicine and Surgery (DiMeC), University of Parma, Parma, Italy
| | - Martina Chiu
- Department of Medicine and Surgery (DiMeC), University of Parma, Parma, Italy
| | - Verena Ellerkamp
- Department of Paediatric Surgery and Paediatric Urology, University Children's Hospital, Eberhard Karls University Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany
| | - Marcus O Scharpf
- Institute for Pathology and Neuropathology, Department of General Pathology and Pathological Anatomy, Eberhard Karls University Tuebingen, Liebermeisterstr. 8, 72076, Tuebingen, Germany
| | - Philip Sander
- Institute for Pathology and Neuropathology, Department of General Pathology and Pathological Anatomy, Eberhard Karls University Tuebingen, Liebermeisterstr. 8, 72076, Tuebingen, Germany
| | - Evi Schmid
- Department of Paediatric Surgery and Paediatric Urology, University Children's Hospital, Eberhard Karls University Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany
| | - Steven W Warmann
- Department of Paediatric Surgery and Paediatric Urology, University Children's Hospital, Eberhard Karls University Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany
| | - Jörg Fuchs
- Department of Paediatric Surgery and Paediatric Urology, University Children's Hospital, Eberhard Karls University Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany
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Cho YJ, Namgoong JM, Kwon HH, Kwon YJ, Kim DY, Kim SC. The Advantages of Indocyanine Green Fluorescence Imaging in Detecting and Treating Pediatric Hepatoblastoma: A Preliminary Experience. Front Pediatr 2021; 9:635394. [PMID: 33718305 PMCID: PMC7952306 DOI: 10.3389/fped.2021.635394] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/08/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Currently, indocyanine green (ICG) fluorescence imaging enables radical surgical resection in hepatoblastoma (HB) and has beneficial uses; however, its usage in pediatric patients is still limited. Methods: From 2015 to 2019, 17 hepatoblastoma patients underwent 22 fluorescence-guided surgery using ICG. ICG (0.3 mg/kg) was intravenously injected 24-48 h before the operation. With ICG/NIR camera, intraoperative identification of biological structures and demarcation of mass were conducted. Results: ICG fluorescence-guided surgery was performed for hepatoblastoma in 22 cases: 16, 1, and 2 cases underwent anatomic resection, partial hepatectomy, and liver transplantation, respectively. Six patients accompanied lung metastasis at the time of surgery, and two patients underwent lung surgery using ICG. The median interval from ICG injection to surgery was 38.3 h (range, 20.5-50.3 h). The median tumor size was 36.5 mm (range, 2-132 mm). According to the pathologic finding, the median safety margin was secured for 6 mm (range, 0-11 mm) and there was no residual finding at the liver at the follow-up computed tomography (CT). Conclusions: ICG fluorescence imaging in children with HB was feasible and safe for tumor demarcation and enhancing the accuracy of radical tumor resection.
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Affiliation(s)
- Yu Jeong Cho
- Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jung-Man Namgoong
- Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea
| | - Hyun Hee Kwon
- Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea
| | - Yong Jae Kwon
- Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea
| | - Dae Yeon Kim
- Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea
| | - Seong Chul Kim
- Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea
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8
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Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications. J Hepatol 2020; 73:328-341. [PMID: 32240714 DOI: 10.1016/j.jhep.2020.03.025] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 03/11/2020] [Accepted: 03/13/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Herein, we aimed to uncover the mechanisms of HB pathobiology and to identify new biomarkers and therapeutic targets in a move towards precision medicine for patients with advanced HB. METHODS We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically annotated samples from 113 patients with HB, using high-throughput technologies. RESULTS We discovered a widespread epigenetic footprint of HB that includes hyperediting of the tumor suppressor BLCAP concomitant with a genome-wide dysregulation of RNA editing and the overexpression of mainly non-coding genes of the oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, we identified 2 epigenomic clusters (Epi-CA, Epi-CB) with distinct degrees of DNA hypomethylation and CpG island hypermethylation that are associated with the C1/C2/C2B transcriptomic subtypes. Based on these findings, we defined the first molecular risk stratification of HB (MRS-HB), which encompasses 3 main prognostic categories and improves the current clinical risk stratification approach. The MRS-3 category (28%), defined by strong 14q32 locus expression and Epi-CB methylation features, was characterized by CTNNB1 and NFE2L2 mutations, a progenitor-like phenotype and clinical aggressiveness. Finally, we identified choline kinase alpha as a promising therapeutic target for intermediate and high-risk HBs, as its inhibition in HB cell lines and patient-derived xenografts strongly abrogated tumor growth. CONCLUSIONS These findings provide a detailed insight into the molecular features of HB and could be used to improve current clinical stratification approaches and to develop treatments for patients with HB. LAY SUMMARY Hepatoblastoma is a rare childhood liver cancer that has been understudied. We have used cutting-edge technologies to expand our molecular knowledge of this cancer. Our biological findings can be used to improve clinical management and pave the way for the development of novel therapies for this cancer.
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Underhill GH, Khetani SR. Emerging trends in modeling human liver disease in vitro. APL Bioeng 2019; 3:040902. [PMID: 31893256 PMCID: PMC6930139 DOI: 10.1063/1.5119090] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 11/29/2019] [Indexed: 12/18/2022] Open
Abstract
The liver executes 500+ functions, such as protein synthesis, xenobiotic metabolism, bile production, and metabolism of carbohydrates/fats/proteins. Such functions can be severely degraded by drug-induced liver injury, nonalcoholic fatty liver disease, hepatitis B and viral infections, and hepatocellular carcinoma. These liver diseases, which represent a significant global health burden, are the subject of novel drug discovery by the pharmaceutical industry via the use of in vitro models of the human liver, given significant species-specific differences in disease profiles and drug outcomes. Isolated primary human hepatocytes (PHHs) are a physiologically relevant cell source to construct such models; however, these cells display a rapid decline in the phenotypic function within conventional 2-dimensional monocultures. To address such a limitation, several engineered platforms have been developed such as high-throughput cellular microarrays, micropatterned cocultures, self-assembled spheroids, bioprinted tissues, and perfusion devices; many of these platforms are being used to coculture PHHs with liver nonparenchymal cells to model complex cell cross talk in liver pathophysiology. In this perspective, we focus on the utility of representative platforms for mimicking key features of liver dysfunction in the context of chronic liver diseases and liver cancer. We further discuss pending issues that will need to be addressed in this field moving forward. Collectively, these in vitro liver disease models are being increasingly applied toward the development of new therapeutics that display an optimal balance of safety and efficacy, with a focus on expediting development, reducing high costs, and preventing harm to patients.
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Affiliation(s)
- Gregory H. Underhill
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
| | - Salman R. Khetani
- Department of Bioengineering, University of Illinois at Chicago, Chicago, Illinois 60607, USA
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10
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Yamada Y, Ohno M, Fujino A, Kanamori Y, Irie R, Yoshioka T, Miyazaki O, Uchida H, Fukuda A, Sakamoto S, Kasahara M, Matsumoto K, Fuchimoto Y, Hoshino K, Kuroda T, Hishiki T. Fluorescence-Guided Surgery for Hepatoblastoma with Indocyanine Green. Cancers (Basel) 2019; 11:cancers11081215. [PMID: 31434361 PMCID: PMC6721588 DOI: 10.3390/cancers11081215] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 08/15/2019] [Accepted: 08/16/2019] [Indexed: 01/06/2023] Open
Abstract
Fluorescence-guided surgery with indocyanine green (ICG) for malignant hepatic tumors has been gaining more attention with technical advancements. Since hepatoblastomas (HBs) possess similar features to hepatocellular carcinoma, fluorescence-guided surgery can be used for HBs, as aggressive surgical resection, even for distant metastases of HBs, often contributes positively to R0 (complete) resection and subsequent patient survival. Despite a few caveats, fluorescence-guided surgery allows for the more sensitive identification of lesions that may go undetected by conventional imaging or be invisible macroscopically. This leads to precise resection of distant metastatic tumors as well as primary liver tumors.
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Affiliation(s)
- Yohei Yamada
- Department of Pediatric Surgery, National Center for Child Health and Development, Tokyo 157-0074, Japan.
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
| | - Michinobu Ohno
- Department of Pediatric Surgery, National Center for Child Health and Development, Tokyo 157-0074, Japan
| | - Akihiro Fujino
- Department of Pediatric Surgery, National Center for Child Health and Development, Tokyo 157-0074, Japan
| | - Yutaka Kanamori
- Department of Pediatric Surgery, National Center for Child Health and Development, Tokyo 157-0074, Japan
| | - Rie Irie
- Department of Pathology, National Center for Child Health and Development, Tokyo 157-0074, Japan
| | - Takako Yoshioka
- Department of Pathology, National Center for Child Health and Development, Tokyo 157-0074, Japan
| | - Osamu Miyazaki
- Department of Radiology, National Center for Child Health and Development, Tokyo 157-0074, Japan
| | - Hajime Uchida
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo 157-0074, Japan
| | - Akinari Fukuda
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo 157-0074, Japan
| | - Seisuke Sakamoto
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo 157-0074, Japan
| | - Mureo Kasahara
- Center for Organ Transplantation, National Center for Child Health and Development, Tokyo 157-0074, Japan
| | - Kimikazu Matsumoto
- Children Cancer Center, National Center for Child Health and Development, Tokyo 157-0074, Japan
| | - Yasushi Fuchimoto
- Department of Pediatric Surgery, International University of Health and Welfare, Chiba 286-0048, Japan
| | - Ken Hoshino
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Tatsuo Kuroda
- Department of Pediatric Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Tomoro Hishiki
- Division of Surgical Oncology, National Center for Child Health and Development, Tokyo 157-0074, Japan
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11
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Eberherr C, Beck A, Vokuhl C, Becker K, Häberle B, Von Schweinitz D, Kappler R. Targeting excessive MYCN expression using MLN8237 and JQ1 impairs the growth of hepatoblastoma cells. Int J Oncol 2019; 54:1853-1863. [PMID: 30864675 DOI: 10.3892/ijo.2019.4741] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 01/23/2019] [Indexed: 11/06/2022] Open
Abstract
Hepatoblastoma (HB) is the most common liver tumor in children under the age of 3 years worldwide. While many patients achieve good outcomes with surgical resection and conventional chemotherapy, there is still a high‑risk population that exhibits a poor treatment response and unfavorable prognosis, which warrants the search for novel treatment options. In recent years, it has become clear that genetic events alone are not sufficient to explain the aggressive phenotype of this embryonal malignancy. Instead, epigenetic modifications and aberrant gene expression seem to be key drivers of HB. In the present study, expression analyses such as reverse transcription‑quantitative polymerase chain reaction revealed that the oncogene, MYCN proto‑oncogene basic‑helix‑loop‑helix transcription factor (MYCN) was upregulated in HB and other pediatric liver tumors, due to the transcriptional activity of its antisense transcript MYCN opposite strand (MYCNOS). Pyrosequencing demonstrated the hypomethylated regions in the promoter of MYCN and MYCNOS, suggesting that an epigenetic mechanism may underlie the induction of aberrant expression. Transient MYCN knockdown in HB cells resulted in growth inhibition over time. In addition, treating HB cells with the MYCN inhibitors JQ1 and MLN8237 led to the significant downregulation of MYCN either at the mRNA or protein levels, respectively. The underlying mechanism of action of the two inhibitors was revealed to be associated with the induction of dose‑dependent growth arrest, by arresting cells at either the G1/G0 or G2 phase. Furthermore, MLN8237 and JQ1 were able to cause spindle disturbances and/or apoptosis in HB cells. The present results suggest that MYCN may be a promising biomarker for HB and a potential therapeutic target in patients with tumors overexpressing MYCN.
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Affiliation(s)
- Corinna Eberherr
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, D‑80337 Munich, Germany
| | - Alexander Beck
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, D‑80337 Munich, Germany
| | - Christian Vokuhl
- Institute of Paidopathology, Pediatric Tumor Registry, Christian‑Albrecht's‑University Kiel, D‑24105 Kiel, Germany
| | - Kristina Becker
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, D‑80337 Munich, Germany
| | - Beate Häberle
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, D‑80337 Munich, Germany
| | - Dietrich Von Schweinitz
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, D‑80337 Munich, Germany
| | - Roland Kappler
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, D‑80337 Munich, Germany
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12
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Bonomini F, Borsani E, Favero G, Rodella LF, Rezzani R. Dietary Melatonin Supplementation Could Be a Promising Preventing/Therapeutic Approach for a Variety of Liver Diseases. Nutrients 2018; 10:nu10091135. [PMID: 30134592 PMCID: PMC6164189 DOI: 10.3390/nu10091135] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 08/14/2018] [Accepted: 08/17/2018] [Indexed: 02/07/2023] Open
Abstract
In the therapeutic strategies, the role of diet is a well-established factor that can also have an important role in liver diseases. Melatonin, identified in animals, has many antioxidant properties and it was after discovered also in plants, named phytomelatonin. These substances have a positive effect during aging and in pathological conditions too. In particular, it is important to underline that the amount of melatonin produced by pineal gland in human decreases during lifetime and its reduction in blood could be related to pathological conditions in which mitochondria and oxidative stress play a pivotal role. Moreover, it has been indicated that melatonin/phytomelatonin containing foods may provide dietary melatonin, so their ingestion through balanced diets could be sufficient to confer health benefits. In this review, the classification of liver diseases and an overview of the most important aspects of melatonin/phytomelatonin, concerning the differences among their synthesis, their presence in foods and their role in health and diseases, are summarized. The findings suggest that melatonin/phytomelatonin supplementation with diet should be considered important in preventing different disease settings, in particular in liver. Currently, more studies are needed to strengthen the potential beneficial effects of melatonin/phytomelatonin in liver diseases and to better clarify the molecular mechanisms of action.
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Affiliation(s)
- Francesca Bonomini
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
- Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs-(ARTO)", University of Brescia, 25123 Brescia, Italy.
| | - Elisa Borsani
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
- Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs-(ARTO)", University of Brescia, 25123 Brescia, Italy.
| | - Gaia Favero
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
| | - Luigi F Rodella
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
- Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs-(ARTO)", University of Brescia, 25123 Brescia, Italy.
| | - Rita Rezzani
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
- Interdipartimental University Center of Research "Adaption and Regeneration of Tissues and Organs-(ARTO)", University of Brescia, 25123 Brescia, Italy.
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13
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Dubbink HJ, Hollink IHIM, Avenca Valente C, Wang W, Liu P, Doukas M, van Noesel MM, Dinjens WNM, Wagner A, Smits R. A novel tissue-based ß-catenin gene and immunohistochemical analysis to exclude familial adenomatous polyposis among children with hepatoblastoma tumors. Pediatr Blood Cancer 2018; 65:e26991. [PMID: 29446530 DOI: 10.1002/pbc.26991] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 12/28/2017] [Accepted: 01/02/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND The Wnt/β-catenin pathway plays a central role in the pathogenesis of most hepatoblastomas (HBs), that is, up to 60-80% carry activating CTNNB1 mutations. HBs can however also be the first manifestation of familial adenomatous polyposis (FAP). As this is a severe disease, it is important for the patient and related family members to firmly exclude FAP at an early stage. Current diagnosis largely depends on APC germline mutation detection on genomic DNA, which is associated with 10-20% false-negative results. Here, we establish and validate a tissue-based β-catenin gene and immunohistochemical analysis, which complements germline mutation screening to exclude the diagnosis of FAP among HB patients. METHODS Tumor tissues of 18 HB patients, including three FAP cases were subjected to CTNNB1 exon 3 mutational analysis and immunohistochemistry comparing staining patterns for total and exon 3 specific β-catenin antibodies. RESULTS Our novel tissue-based method reliably identified all three FAP patients. Their tumors were characterized by a wild-type exon 3 sequence and a comparable nuclear staining for both antibodies. In contrast, the non-FAP tumors carried missense CTNNB1 mutations combined with a clearly reduced staining for the exon 3 antibody, or complete loss of staining in case of lesions with exon 3 deletions. CONCLUSION We have successfully established and validated a novel ß-catenin gene and immunohistochemical diagnostic method, which, when combined with routine germline DNA testing, allows the exclusion of the diagnosis of FAP among HB patients.
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Affiliation(s)
- Hendrikus J Dubbink
- Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Iris H I M Hollink
- Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Carolina Avenca Valente
- Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Wenhui Wang
- Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Pengyu Liu
- Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Michail Doukas
- Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Max M van Noesel
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Winand N M Dinjens
- Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Anja Wagner
- Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Ron Smits
- Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
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14
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Beck A, Trippel F, Wagner A, Joppien S, Felle M, Vokuhl C, Schwarzmayr T, Strom TM, von Schweinitz D, Längst G, Kappler R. Overexpression of UHRF1 promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma. Clin Epigenetics 2018; 10:27. [PMID: 29507645 PMCID: PMC5833129 DOI: 10.1186/s13148-018-0462-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 02/21/2018] [Indexed: 02/02/2023] Open
Abstract
Background Hepatoblastoma (HB) is the most common liver tumor of childhood and occurs predominantly within the first 3 years of life. In accordance to its early manifestation, HB has been described to display an extremely low mutation rate. As substitute, epigenetic modifiers seem to play an exceptional role in its tumorigenesis, which holds promise to develop targeted therapies and establish biomarkers for patient risk stratification. Results We examined the role of a newly described protein complex consisting of three epigenetic regulators, namely E3 ubiquitin-like containing PHD and RING finger domain 1 (UHRF1), ubiquitin-specific-processing protease 7 (USP7), and DNA methyltransferase 1 (DNMT1), in HB. We found the complex to be located on the promoter regions of the pivotal HB-associated tumor suppressor genes (TSGs) HHIP, IGFBP3, and SFRP1 in HB cells, thereby leading to strong repression through DNA methylation and histone modifications. Consequently, knockdown of UHRF1 led to DNA demethylation and loss of the repressive H3K9me2 histone mark at the TSG loci with their subsequent transcriptional reactivation. The observed growth impairment of HB cells upon UHRF1 knockdown could be attributed to reduced expression of genes involved in cell cycle progression, negative regulation of cell death, LIN28B signaling, and the adverse 16-gene signature, as revealed by global RNA sequencing. Clinically, overexpression of UHRF1 in primary tumor tissues was significantly associated with poor survival and the prognostic high-risk 16-gene signature. Conclusion These findings suggest that UHRF1 is critical for aberrant TSG silencing and sustained growth signaling in HB and that UHRF1 overexpression levels might serve as a prognostic biomarker and potential molecular target for HB patients. Electronic supplementary material The online version of this article (10.1186/s13148-018-0462-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Alexander Beck
- 1Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Lindwurmstr. 2a, 80337 Munich, Germany
| | - Franziska Trippel
- 1Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Lindwurmstr. 2a, 80337 Munich, Germany
| | - Alexandra Wagner
- 1Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Lindwurmstr. 2a, 80337 Munich, Germany
| | - Saskia Joppien
- 1Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Lindwurmstr. 2a, 80337 Munich, Germany
| | - Max Felle
- 2Department of Biochemistry III, University Regensburg, Regensburg, Germany
| | - Christian Vokuhl
- 3Institute of Paidopathology, Pediatric Tumor Registry, Christian-Albrecht's-University Kiel, Kiel, Germany
| | - Thomas Schwarzmayr
- 4Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.,5Institute of Human Genetics, Technische Universität München, Munich, Germany
| | - Tim M Strom
- 4Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.,5Institute of Human Genetics, Technische Universität München, Munich, Germany
| | - Dietrich von Schweinitz
- 1Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Lindwurmstr. 2a, 80337 Munich, Germany
| | - Gernot Längst
- 2Department of Biochemistry III, University Regensburg, Regensburg, Germany
| | - Roland Kappler
- 1Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Lindwurmstr. 2a, 80337 Munich, Germany
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15
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Aran G, Sanjurjo L, Barcena C, Simon‐Coma M, Téllez É, Vázquez‐Vitali M, Garrido M, Guerra L, Díaz E, Ojanguren I, Elortza F, Planas R, Sala M, Armengol C, Sarrias M. CD5L is upregulated in hepatocellular carcinoma and promotes liver cancer cell proliferation and antiapoptotic responses by binding to HSPA5 (GRP78). FASEB J 2018; 32:3878-3891. [DOI: 10.1096/fj.201700941rr] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Gemma Aran
- Innate Immunity GroupHealth Sciences Research Institute Germans Trias i Pujol (IGTP)BadalonaSpain
| | - Lucía Sanjurjo
- Innate Immunity GroupHealth Sciences Research Institute Germans Trias i Pujol (IGTP)BadalonaSpain
- Network for Biomédical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM)MadridSpain
| | - Cristina Barcena
- Innate Immunity GroupHealth Sciences Research Institute Germans Trias i Pujol (IGTP)BadalonaSpain
| | - Marina Simon‐Coma
- Childhood Liver Oncology GroupProgram of Predictive and Personalized Medicine of Cancer (PMPCC)IGTPBadalonaSpain
- Network for Biomedical Research in Hepatic and Digestive Diseases (CIBEREHD)Spain
| | - Érica Téllez
- Innate Immunity GroupHealth Sciences Research Institute Germans Trias i Pujol (IGTP)BadalonaSpain
| | - Maria Vázquez‐Vitali
- Childhood Liver Oncology GroupProgram of Predictive and Personalized Medicine of Cancer (PMPCC)IGTPBadalonaSpain
| | - Marta Garrido
- Pathology DepartmentVall D'Hebron HospitalBarcelonaSpain
| | - Laura Guerra
- Pathology DepartmentHospital Universitario La PazMadridSpain
| | - Esther Díaz
- Pathology DepartmentJosep Trueta HospitalGironaSpain
| | - Isabel Ojanguren
- Pathology DepartmentHospital Universitari Germans Trias i Pujol Hospital (HUGTiP)BadalonaSpain
| | - Felix Elortza
- Network for Biomedical Research in Hepatic and Digestive Diseases (CIBEREHD)Spain
- Proteomics PlatformCenter for Cooperative Research in Biosciences (CIC bioGUNE)DerioSpain
| | - Ramon Planas
- Network for Biomedical Research in Hepatic and Digestive Diseases (CIBEREHD)Spain
- Gastroenterology DepartmentHospital Universitari Germans Trias i Pujol Hospital (HUGTiP)BadalonaSpain
| | - Margarita Sala
- Network for Biomedical Research in Hepatic and Digestive Diseases (CIBEREHD)Spain
- Gastroenterology DepartmentHospital Universitari Germans Trias i Pujol Hospital (HUGTiP)BadalonaSpain
| | - Carolina Armengol
- Childhood Liver Oncology GroupProgram of Predictive and Personalized Medicine of Cancer (PMPCC)IGTPBadalonaSpain
- Network for Biomedical Research in Hepatic and Digestive Diseases (CIBEREHD)Spain
| | - Maria‐Rosa Sarrias
- Innate Immunity GroupHealth Sciences Research Institute Germans Trias i Pujol (IGTP)BadalonaSpain
- Network for Biomedical Research in Hepatic and Digestive Diseases (CIBEREHD)Spain
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16
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Abdelahamid S, Khedr RA, El Wakeel M, Younes A, Ahmed G, Elkinaai N, Tantawy M, Hafez HA. Hepatoblastoma in Developing Countries; Eight Years of Single Centre Experience. ACTA ACUST UNITED AC 2018. [DOI: 10.4236/jct.2018.910065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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17
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Abstract
Hepatoblastoma is the most common primary malignant hepatic tumor of infancy and childhood, occurring predominantly in the first two years of life. The management of hepatoblastoma has changed markedly over the last 3 decades; neoadjuvant chemotherapy is now standard, particularly in unresectable tumors resulting in considerable preoperative tumor shrinkage and sometimes near total ablation of the tumor. A 20 month old infant was incidentally found to have a 7.6cm right sided retroperitoneal tumor on routine screening ultrasonography for left ureteral stenosis. Serum alpha fetoprotein was elevated. Biopsy revealed hepatoblastoma, mixed epithelial and embryonal type without mesenchymal elements. He underwent neoadjuvant chemotherapy. Although the tumor had decreased considerably in size, close proximity to major vascular structures precluded safe resection. Liver transplantation was performed; the explanted liver showed complete tumor necrosis with no residual malignancy. The postoperative course was uncomplicated and he is continuing on sixth cycle of chemotherapy.
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Affiliation(s)
- Divya Sharma
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, United States
| | - Girish Subbarao
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, United States
| | - Romil Saxena
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, United States.
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18
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Dong R, Zheng S, Dong K. Distinguishing Among Pediatric Hepatoblastomas, Transitional Liver Cell Tumors, and Hepatocellular Carcinomas and Using Appropriate Chemotherapy Regimens. J Clin Oncol 2016; 35:115-116. [PMID: 28034077 DOI: 10.1200/jco.2016.66.9689] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Rui Dong
- Rui Dong, Shan Zheng, and Kuiran Dong, Children's Hospital of Fudan University, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, People's Republic of China
| | - Shan Zheng
- Rui Dong, Shan Zheng, and Kuiran Dong, Children's Hospital of Fudan University, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, People's Republic of China
| | - Kuiran Dong
- Rui Dong, Shan Zheng, and Kuiran Dong, Children's Hospital of Fudan University, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, People's Republic of China
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19
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Abstract
This article aims to give an overview of pediatric liver tumors; in particular of the two most frequently occurring groups of hepatoblastomas and hepatocellular carcinomas. Focus lays on achievements gained through worldwide collaboration. We present recent advances in insight, treatment results, and future questions to be asked. Increasing international collaboration between the four major Pediatric Liver Tumor Study Groups (SIOPEL/GPOH, COG, and JPLT) may serve as a paradigm to approach rare tumors. This international effort has been catalyzed by the Children's Hepatic tumor International Collaboration (CHIC) formation of a large collaborative database. Interrogation of this database has led to a new universal risk stratification system for hepatoblastoma using PRETEXT/POSTTEXT staging as a backbone. Pathologists in this international collaboration have established a new histopathological consensus classification for pediatric liver tumors. Concomitantly there have been advances in chemotherapy options, an increased role of liver transplantation for unresectable tumors, and a web portal system developed at www.siopel.org for international education, consultation, and collaboration. These achievements will be further tested and validated in the upcoming Paediatric Hepatic International Tumour Trial (PHITT).
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Affiliation(s)
- Daniel C Aronson
- Department of Paediatric Surgery, Noah's Ark Children's Hospital for Wales, University Hospital of Wales, Cardiff and Vale University Health Board NHS Trust, Cardiff CF14 4XW, UK.
| | - Rebecka L Meyers
- Division of Pediatric Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA
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20
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Nicolle D, Fabre M, Simon-Coma M, Gorse A, Kappler R, Nonell L, Mallo M, Haidar H, Déas O, Mussini C, Guettier C, Redon MJ, Brugières L, Ghigna MR, Fadel E, Galmiche-Rolland L, Chardot C, Judde JG, Armengol C, Branchereau S, Cairo S. Patient-derived mouse xenografts from pediatric liver cancer predict tumor recurrence and advise clinical management. Hepatology 2016; 64:1121-35. [PMID: 27115099 DOI: 10.1002/hep.28621] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 03/25/2016] [Accepted: 04/20/2016] [Indexed: 01/30/2023]
Abstract
UNLABELLED Identification of new treatments for relapsing pediatric cancer is an unmet clinical need and a societal challenge. Liver cancer occurrence in infancy, 1.5 for million children per year, falls far below the threshold of interest for dedicated drug development programs, and this disease is so rare that it is very difficult to gather enough children into a phase II clinical trial. Here, we present the establishment of an unprecedented preclinical platform of 24 pediatric liver cancer patient-derived xenografts (PLC-PDXs) from 20 hepatoblastomas (HBs), 1 transitional liver cell tumor (TCLT), 1 hepatocellular carcinoma, and 2 malignant rhabdoid tumors. Cytogenetic array and mutational analysis of the parental tumors and the corresponding PLC-PDXs show high conservation of the molecular features of the parental tumors. The histology of PLC-PDXs is strikingly similar to that observed in primary tumors and recapitulates the heterogeneity of recurrent disease observed in the clinic. Tumor growth in the mouse is strongly associated with elevated circulating alpha-fetoprotein (AFP), low rate of necrosis/fibrosis after treatment, and gain of chromosome 20, all indicators of resistance to chemotherapy and poor outcome. Accordingly, the ability of a tumor to generate PLC-PDX is predictive of poor prognosis. Exposure of PLC-PDXs to standards of care or therapeutic options already in use for other pediatric malignancies revealed unique response profiles in these models. Among these, the irinotecan/temozolomide combination induced strong tumor regression in the TCLT and in a model derived from an AFP-negative relapsing HB. CONCLUSION These results provide evidence that PLC-PDX preclinical platform can strongly contribute to accelerate the identification and diversification of anticancer treatment for aggressive subtypes of pediatric liver cancer. (Hepatology 2016;64:1121-1135).
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Affiliation(s)
| | - Monique Fabre
- Anathomic Pathology Department, Hôpital Necker Enfants Malades, Paris, France
| | - Marina Simon-Coma
- Childhood Liver Oncology group (c-LOG), Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | | | - Roland Kappler
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Lara Nonell
- Microarray Analysis Facility, Institut Hospital del Mar Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - Mar Mallo
- Affymetrix Microarrays Platform and MDS Group, Josep Carreras Leukaemia Research Institute (IJC), ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), Badalona, Spain
| | - Hazar Haidar
- Pharmacogenetic, Molecular Biochemistry and Hormonology Service, Bicêtre Hospital, Paris Sud University, Le Kremlin Bicêtre, France
| | | | - Charlotte Mussini
- Anatomic pathology and Cytopathology Department, Bicêtre Hospital, Paris Sud University, Le Kremlin Bicêtre, France
| | - Catherine Guettier
- Anatomic pathology and Cytopathology Department, Bicêtre Hospital, Paris Sud University, Le Kremlin Bicêtre, France
| | - Marie-José Redon
- Anatomic pathology and Cytopathology Department, Bicêtre Hospital, Paris Sud University, Le Kremlin Bicêtre, France
| | - Laurence Brugières
- Department of Childhood and Adolescence Oncology, Gustave Roussy Cancer Campus, Villejuif, France
| | - Maria Rosa Ghigna
- Department of Pathology, Marie Lannelongue Hospital, Le Plessis Robinson, France
| | - Elie Fadel
- Department of Thoracic and Vascular Surgery, Hôpital Marie Lannelongue, Le Plessis Robinson, France
| | | | - Christophe Chardot
- Department of Pediatric Surgery, Hôpital Necker Enfants Malades, Paris, France
| | | | - Carolina Armengol
- Childhood Liver Oncology group (c-LOG), Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Sophie Branchereau
- Department of Pediatric Surgery, Bicêtre Hospital, Paris Sud University, Le Kremlin Bicêtre, France
| | - Stefano Cairo
- XenTech, 4 rue Pierre Fontaine, Evry, France. .,LTTA Center, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Italy.
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21
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Scarzello AJ, Jiang Q, Back T, Dang H, Hodge D, Hanson C, Subleski J, Weiss JM, Stauffer JK, Chaisaingmongkol J, Rabibhadana S, Ruchirawat M, Ortaldo J, Wang XW, Norris PS, Ware CF, Wiltrout RH. LTβR signalling preferentially accelerates oncogenic AKT-initiated liver tumours. Gut 2016; 65. [PMID: 26206664 PMCID: PMC5036232 DOI: 10.1136/gutjnl-2014-308810] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The relative contributions of inflammatory signalling and sequential oncogenic dysregulation driving liver cancer pathogenesis remain incompletely understood. Lymphotoxin-β receptor (LTβR) signalling is critically involved in hepatitis and liver tumorigenesis. Therefore, we explored the interdependence of inflammatory lymphotoxin signalling and specific oncogenic pathways in the progression of hepatic cancer. DESIGN Pathologically distinct liver tumours were initiated by hydrodynamic transfection of oncogenic V-Akt Murine Thymoma Viral Oncogene Homolog 1 (AKT)/β-catenin or AKT/Notch expressing plasmids. To investigate the relationship of LTβR signalling and specific oncogenic pathways, LTβR antagonist (LTβR-Fc) or agonist (anti-LTβR) were administered post oncogene transfection. Initiated livers/tumours were investigated for changes in oncogene expression, tumour proliferation, progression, latency and pathology. Moreover, specific LTβR-mediated molecular events were investigated in human liver cancer cell lines and through transcriptional analyses of samples from patients with intrahepatic cholangiocarcinoma (ICC). RESULTS AKT/β-catenin-transfected livers displayed increased expression of LTβ and LTβR, with antagonism of LTβR signalling reducing tumour progression and enhancing survival. Conversely, enforced LTβR-activation of AKT/β-catenin-initiated tumours induced robust increases in proliferation and progression of hepatic tumour phenotypes in an AKT-dependent manner. LTβR-activation also rapidly accelerated ICC progression initiated by AKT/Notch, but not Notch alone. Moreover, LTβR-accelerated development coincides with increases of Notch, Hes1, c-MYC, pAKT and β-catenin. We further demonstrate LTβR signalling in human liver cancer cell lines to be a regulator of Notch, pAKTser473 and β-catenin. Transcriptome analysis of samples from patients with ICC links increased LTβR network expression with poor patient survival, increased Notch1 expression and Notch and AKT/PI3K signalling. CONCLUSIONS Our findings link LTβR and oncogenic AKT signalling in the development of ICC.
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Affiliation(s)
- Anthony J Scarzello
- Cancer and Inflamation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Qun Jiang
- Cancer and Inflamation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Timothy Back
- Cancer and Inflamation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Hien Dang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Deborah Hodge
- Cancer and Inflamation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Charlotte Hanson
- Cancer and Inflamation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Jeffrey Subleski
- Cancer and Inflamation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Jonathan M Weiss
- Cancer and Inflamation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Jimmy K Stauffer
- Cancer and Inflamation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | | | | | | | - John Ortaldo
- Cancer and Inflamation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Paula S Norris
- Infectious and Inflammatory Diseases Research Center, Sanford Burnham Medical Research Institute, La Jolla, California, USA
| | - Carl F Ware
- Infectious and Inflammatory Diseases Research Center, Sanford Burnham Medical Research Institute, La Jolla, California, USA
| | - Robert H Wiltrout
- Cancer and Inflamation Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
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22
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He J, Guo X, Sun L, Wang N, Bao J. Regulatory network analysis of genes and microRNAs in human hepatoblastoma. Oncol Lett 2016; 12:4099-4106. [PMID: 27895778 DOI: 10.3892/ol.2016.5196] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 01/11/2016] [Indexed: 01/03/2023] Open
Abstract
Hepatoblastoma (HB) is a common type of primary tumor in children. Previous studies have examined the expression of genes, including transcription factors (TFs), target genes, host genes and microRNAs (miRNAs or miRs) associated with HB. However, the regulatory pathways of miRNAs and genes remain unclear. In the present study, a novel perspective is proposed, which focuses on HB and the associated regulatory pathways, to construct three networks at various levels, including a differentially expressed network, an associated network and a global network. Genes and miRNAs are considered as key factors in the network. In the three networks, the associations between each pair of factors, including TFs that regulate miRNAs, miRNAs that interact with target genes and miRNAs that are located at host genes, were analyzed. The differentially expressed network is considered to be the most crucial of the three networks. All factors in the differentially expressed network were mutated or differentially expressed, which indicated that the majority of the factors were cancerogenic factors that may lead to HB. In addition, the network contained numerous abnormal linkages that may trigger HB. If the expression of each factor was corrected to a normal level, HB may be successfully treated. The associated network included more HB-associated genes and miRNAs, and was useful for analyzing the pathogenesis of HB. By analyzing these close associations, the first and the last factor of the regulatory pathways were revealed to have important roles in HB. For example, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) was observed to regulate Homo sapiens (hsa)-miR-221, hsa-miR-18a and hsa-miR-17-5p, but no miRNAs targeted MYCN. In conclusion, the pathways and mechanisms underlying HB were expounded in the present study, which proposed a fundamental hypothesis for additional studies.
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Affiliation(s)
- Jimin He
- College of Computer Science and Technology, Jilin University, Changchun, Jilin 130012, P.R. China; Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, Jilin 130012, P.R. China
| | - Xiaoxin Guo
- College of Computer Science and Technology, Jilin University, Changchun, Jilin 130012, P.R. China; College of Software, Jilin University, Changchun, Jilin 130012, P.R. China; Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, Jilin 130012, P.R. China
| | - Linlin Sun
- College of Software, Jilin University, Changchun, Jilin 130012, P.R. China; Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, Jilin 130012, P.R. China
| | - Ning Wang
- College of Computer Science and Technology, Jilin University, Changchun, Jilin 130012, P.R. China; Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, Jilin 130012, P.R. China
| | - Jiwei Bao
- College of Software, Jilin University, Changchun, Jilin 130012, P.R. China; Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, Jilin 130012, P.R. China
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23
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Bahnassy AA, Fawzy M, El-Wakil M, Zekri ARN, Abdel-Sayed A, Sheta M. Aberrant expression of cancer stem cell markers (CD44, CD90, and CD133) contributes to disease progression and reduced survival in hepatoblastoma patients: 4-year survival data. Transl Res 2015; 165:396-406. [PMID: 25168019 DOI: 10.1016/j.trsl.2014.07.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 07/03/2014] [Accepted: 07/28/2014] [Indexed: 10/24/2022]
Abstract
Hepatoblastoma (HB) is an embryonal tumor of the liver in children. Prognosis and response to treatment in HB are highly variable. Cancer stem cells (CSCs) constitute a population of cells, which contribute to the development and progression of many tumors. However, their role in HB is not well defined yet. We assessed the prognostic and predictive values of some CSC markers in HB patients. Protein and messenger RNA expressions of the CSC markers CD133, CD90, and CD44 were assessed in 43 HB patients and 20 normal hepatic tissues using immunohistochemistry and quantitative real-time polymerase chain reaction. The expression levels of these markers were correlated to standard prognostic factors, patients' response to treatment, overall survival (OS), and disease-free survival (DFS). CD44, CD90, and CD133 proteins were detected in 48.8%, 32.6%, and 48.8% compared with 46.5%, 41.7%, and 58.1% RNA, respectively (concordance, 77.8%-96%). None of the normal tissue samples was positive for any of the markers. Significant correlations were reported between α-fetoprotein and both CD44 and CD133 (P = 0.02) as well as between tumor types CD90 and CD133 (P = 0.009). Reduced OS correlated with CD44, CD90, and CD133 expressions (P < 0.001), advanced stage (P < 0.001), response to treatment (P < 0.001), and total excision of the tumor. Reduced DFS correlated with CD44 and CD133 expressions (P < 0.001) only. In conclusion, CD133, CD44, and CD90 could be used as prognostic and predictive markers in HB. High expression of these markers is significantly associated with poor response to treatment and reduced survival. Moreover, complete surgical resection and systemic chemotherapy are essential to achieve good response and prolonged survival, especially in early stage patients.
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Affiliation(s)
- Abeer A Bahnassy
- Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
| | - Mohamed Fawzy
- Pediatric Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mohamed El-Wakil
- Clinical Oncology Department, Faculty of Medicine, Beni-Suef University, Cairo, Egypt
| | - Abdel-Rahman N Zekri
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Ahmed Abdel-Sayed
- Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Marwa Sheta
- Clinical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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24
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Eichenmüller M, Trippel F, Kreuder M, Beck A, Schwarzmayr T, Häberle B, Cairo S, Leuschner I, von Schweinitz D, Strom TM, Kappler R. The genomic landscape of hepatoblastoma and their progenies with HCC-like features. J Hepatol 2014; 61:1312-20. [PMID: 25135868 DOI: 10.1016/j.jhep.2014.08.009] [Citation(s) in RCA: 170] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Revised: 07/15/2014] [Accepted: 08/07/2014] [Indexed: 02/01/2023]
Abstract
BACKGROUND & AIMS Hepatoblastoma (HB) is the most common childhood liver cancer and occasionally presents with histological and clinical features reminiscent of hepatocellular carcinoma (HCC). Identification of molecular mechanisms that drive the neoplastic continuation towards more aggressive HCC phenotypes may help to guide the new stage of targeted therapies. METHODS We performed comprehensive studies on genetic and chromosomal alterations as well as candidate gene function and their clinical relevance. RESULTS Whole-exome sequencing identified HB as a genetically very simple tumour (2.9 mutations per tumour) with recurrent mutations in ß-catenin (CTNNB1) (12/15 cases) and the transcription factor NFE2L2 (2/15 cases). Their HCC-like progenies share the common CTNNB1 mutation, but additionally exhibit a significantly increased mutation number and chromosomal instability due to deletions of the genome guardians RAD17 and TP53, accompanied by telomerase reverse-transcriptase (TERT) promoter mutations. Targeted genotyping of 33 primary tumours and cell lines revealed CTNNB1, NFE2L2, and TERT mutations in 72.5%, 9.8%, and 5.9% of cases, respectively. All NFE2L2 mutations affected residues of the NFE2L2 protein that are recognized by the KEAP1/CUL3 complex for proteasomal degradation. Consequently, cells transfected with mutant NFE2L2 were insensitive to KEAP1-mediated downregulation of NFE2L2 signalling. Clinically, overexpression of the NFE2L2 target gene NQO1 in tumours was significantly associated with metastasis, vascular invasion, the adverse prognostic C2 gene signature, as well as poor outcome. CONCLUSIONS Our study demonstrates the importance of CTNNB1 mutations and NFE2L2-KEAP1 pathway activation in HB development and defines loss of genomic stability and TERT promoter mutations as prominent characteristics of aggressive HB with HCC features.
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Affiliation(s)
- Melanie Eichenmüller
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Franziska Trippel
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Michaela Kreuder
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Alexander Beck
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Thomas Schwarzmayr
- Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, Munich, Germany
| | - Beate Häberle
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | | | - Ivo Leuschner
- Institute of Paidopathology, Pediatric Tumor Registry, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Dietrich von Schweinitz
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Tim M Strom
- Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, Munich, Germany
| | - Roland Kappler
- Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
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25
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Schlachter K, Gyugos M, Halász J, Lendvai G, Baghy K, Garami M, Gyöngyösi B, Schaff Z, Kiss A. High tricellulin expression is associated with better survival in human hepatoblastoma. Histopathology 2014; 65:631-41. [PMID: 24735023 DOI: 10.1111/his.12436] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 04/11/2014] [Indexed: 12/21/2022]
Abstract
AIMS The more differentiated fetal component of hepatoblastoma (HB) is characterized by increased expression of tight junction (TJ) proteins claudin-1 and -2 when compared with embryonal component. Expression patterns of the recently identified TJ protein tricellulin and the epigenetic regulator enzyme EZH2 were investigated in epithelial subtypes of HB and related to survival. METHODS AND RESULTS Twenty-one cases of epithelial HBs subtyped as pure fetal (n = 12) and embryonal/fetal (n = 9), along with 16 non-tumorous samples from surrounding liver, were analysed by immunohistochemistry for tricellulin, β-catenin and EZH2 expression. No significant differences were revealed in overall survival between fetal and embryonal/fetal types of HBs. The fetal component, however, showed considerably increased tricellulin expression while the embryonal component displayed significantly increased nuclear EZH2 positivity, in comparison to other epithelial subtypes and non-tumorous surrounding hepatocytes. Strong nuclear β-catenin staining was notably more frequent in embryonal than in fetal types. High tricellulin expression was associated with significantly increased overall survival (P = 0.03), while elevated EZH2 expression was linked to the presence of distant metastases (P = 0.013). CONCLUSIONS Our data indicate that patients with treated HBs showing high expression of tricellulin have significantly better overall survival, independent of histological subtype. Increased nuclear expression of EZH2 was associated with the presence of distant metastases.
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26
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Mokkapati S, Niopek K, Huang L, Cunniff KJ, Ruteshouser EC, deCaestecker M, Finegold MJ, Huff V. β-catenin activation in a novel liver progenitor cell type is sufficient to cause hepatocellular carcinoma and hepatoblastoma. Cancer Res 2014; 74:4515-25. [PMID: 24848510 DOI: 10.1158/0008-5472.can-13-3275] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) was thought historically to arise from hepatocytes, but gene expression studies have suggested that it can also arise from fetal progenitor cells or their adult progenitor progeny. Here, we report the identification of a unique population of fetal liver progenitor cells in mice that can serve as a cell of origin in HCC development. In the transgenic model used, mice carry the Cited1-CreER(TM)-GFP BAC transgene in which a tamoxifen-inducible Cre (CreER(TM)) and GFP are controlled by a 190-kb 5' genomic region of Cited1, a transcriptional coactivator protein for CBP/p300. Wnt signaling is critical for regulating self-renewal of progenitor/stem cells and has been implicated in the etiology of cancers of rapidly self-renewing tissues, so we hypothesized that Wnt pathway activation in CreER(TM)-GFP(+) progenitors would result in HCC. In livers from the mouse model, transgene-expressing cells represented 4% of liver cells at E11.5 when other markers were expressed, characteristic of the hepatic stem/progenitor cells that give rise to adult hepatocytes, cholangiocytes, and SOX9(+) periductal cells. By 26 weeks of age, more than 90% of Cited1-CreER(TM)-GFP;Ctnnb1(ex3(fl)) mice with Wnt pathway activation developed HCC and, in some cases, hepatoblastomas and lung metastases. HCC and hepatoblastomas resembled their human counterparts histologically, showing activation of Wnt, Ras/Raf/MAPK, and PI3K/AKT/mTOR pathways and expressing relevant stem/progenitor cell markers. Our results show that Wnt pathway activation is sufficient for malignant transformation of these unique liver progenitor cells, offering functional support for a fetal/adult progenitor origin of some human HCC. We believe this model may offer a valuable new tool to improve understanding of the cellular etiology and biology of HCC and hepatoblastomas and the development of improved therapeutics for these diseases.
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Affiliation(s)
- Sharada Mokkapati
- Department of Genetics, University of Texas MD Anderson Cancer Center; Graduate Program in
| | - Katharina Niopek
- Department of Genetics, University of Texas MD Anderson Cancer Center; Graduate Program in
| | - Le Huang
- Department of Genetics, University of Texas MD Anderson Cancer Center; Graduate Program in Genes and Development and
| | - Kegan J Cunniff
- Department of Genetics, University of Texas MD Anderson Cancer Center; Graduate Program in
| | - E Cristy Ruteshouser
- Department of Genetics, University of Texas MD Anderson Cancer Center; Graduate Program in
| | | | - Milton J Finegold
- Baylor College of Medicine and Texas Children's Hospital, Houston, Texas; and
| | - Vicki Huff
- Department of Genetics, University of Texas MD Anderson Cancer Center; Graduate Program in Genes and Development and Human Molecular Genetics, UT-Houston Graduate School of Biomedical Sciences;
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27
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Hackl C, Schlitt HJ, Kirchner GI, Knoppke B, Loss M. Liver transplantation for malignancy: Current treatment strategies and future perspectives. World J Gastroenterol 2014; 20:5331-5344. [PMID: 24833863 PMCID: PMC4017048 DOI: 10.3748/wjg.v20.i18.5331] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Revised: 12/31/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
In 1967, Starzl et al performed the first successful liver transplantation for a patient diagnosed with hepatoblastoma. In the following, liver transplantation was considered ideal for complete tumor resection and potential cure from primary hepatic malignancies. Several reports of liver transplantation for primary and metastatic liver cancer however showed disappointing results and the strategy was soon dismissed. In 1996, Mazzaferro et al introduced the Milan criteria, offering liver transplantation to patients diagnosed with limited hepatocellular carcinoma. Since then, liver transplantation for malignant disease is an ongoing subject of preclinical and clinical research. In this context, several aspects must be considered: (1) Given the shortage of deceased-donor organs, long-term overall and disease free survival should be comparable with results obtained in patients transplanted for non-malignant disease; (2) In this regard, living-donor liver transplantation may in selected patients help to solve the ethical dilemma of optimal individual patient treatment vs organ allocation justice; and (3) Ongoing research focusing on perioperative therapy and anti-proliferative immunosuppressive regimens may further reduce tumor recurrence in patients transplanted for malignant disease and thus improve overall survival. The present review gives an overview of current indications and future perspectives of liver transplantation for malignant disease.
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28
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López-Terrada D, Alaggio R, de Dávila MT, Czauderna P, Hiyama E, Katzenstein H, Leuschner I, Malogolowkin M, Meyers R, Ranganathan S, Tanaka Y, Tomlinson G, Fabrè M, Zimmermann A, Finegold MJ. Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium. Mod Pathol 2014; 27:472-91. [PMID: 24008558 DOI: 10.1038/modpathol.2013.80] [Citation(s) in RCA: 203] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Revised: 02/28/2013] [Accepted: 03/05/2013] [Indexed: 02/07/2023]
Abstract
Liver tumors are rare in children, and their diagnoses may be challenging particularly because of the lack of a current consensus classification system. Systematic central histopathological review of these tumors performed as part of the pediatric collaborative therapeutic protocols has allowed the identification of histologic subtypes with distinct clinical associations. As a result, histopathology has been incorporated within the Children's Oncology Group (COG) protocols, and only in the United States, as a risk-stratification parameter and for patient management. Therefore, the COG Liver Tumor Committee sponsored an International Pathology Symposium in March 2011 to discuss the histopathology and classification of pediatric liver tumors, and hepatoblastoma in particular, and work towards an International Pediatric Liver Tumors Consensus Classification that would be required for international collaborative projects. Twenty-two pathologists and experts in pediatric liver tumors, including those serving as central reviewers for the COG, European Société Internationale d'Oncologie Pédiatrique, Gesellschaft für Pädiatrische Onkologie und Hämatologie, and Japanese Study Group for Pediatric Liver Tumors protocols, as well as pediatric oncologists and surgeons specialized in this field, reviewed more than 50 pediatric liver tumor cases and discussed classic and newly reported entities, as well as criteria for their classification. This symposium represented the first collaborative step to develop a classification that may lead to a common treatment-stratification system incorporating tumor histopathology. A standardized, clinically meaningful classification will also be necessary to allow the integration of new biological parameters and to move towards clinical algorithms based on patient characteristics and tumor genetics, which should improve future patient management and outcome.
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Affiliation(s)
- Dolores López-Terrada
- Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Rita Alaggio
- Division of Pathology, Department of Medicine-DIMED, Pathology Unit, Padova, Italy
| | - Maria T de Dávila
- Departamento de Patologia, Hospital de Pediatría Prof. Dr. J.P. Garrahan, Buenos Aires, Argentina
| | - Piotr Czauderna
- Department of Surgery and Urology for Children and Adolescents, Medical University of Gdansk, Gdansk, Poland
| | - Eiso Hiyama
- Department of Surgery, Natural Science Center for Basic Research and Development, Hiroshima University Hospital, Hiroshima, Japan
| | - Howard Katzenstein
- Aflac Cancer Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Ivo Leuschner
- Institut fur Pathologie, UNI-Klinikum Campus, Kiel, Germany
| | - Marcio Malogolowkin
- Department of Pediatric Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Rebecka Meyers
- Department of Pediatric Surgery, Primary Children's Medical Center, University of Utah, Salt Lake City, UT, USA
| | | | - Yukichi Tanaka
- Division of Pathology, Kanagawa Children's Medical Center, Yokohama, Japan
| | - Gail Tomlinson
- Division of Pediatric Hematology-Oncology, University of Texas Health Science Center, San Antonio, TX, USA
| | - Monique Fabrè
- Department of Pathology, Institut de Cancerologie Gustave Roussy, Villejuif, France
| | | | - Milton J Finegold
- Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
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Fawzy M, Bahnassy A, El-Wakil M, Abdel-Sayed A. Hepatoblastoma Survival and the Prognostic Role of Cancer Stem Cell Markers. INTERNATIONAL JOURNAL OF CANCER THERAPY AND ONCOLOGY 2014. [DOI: 10.14319/ijcto.0201.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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30
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Tanaka Y, Inoue T, Horie H. International pediatric liver cancer pathological classification: current trend. Int J Clin Oncol 2013; 18:946-54. [DOI: 10.1007/s10147-013-0624-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Indexed: 01/16/2023]
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31
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Alonso EM, Ng VL, Anand R, Anderson CD, Ekong UD, Fredericks EM, Furuya KN, Gupta NA, Lerret SM, Sundaram S, Tiao G. The SPLIT research agenda 2013. Pediatr Transplant 2013; 17:412-22. [PMID: 23718800 PMCID: PMC4157303 DOI: 10.1111/petr.12090] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/11/2013] [Indexed: 12/17/2022]
Abstract
This review focuses on active clinical research in pediatric liver transplantation with special emphasis on areas that could benefit from studies utilizing the SPLIT infrastructure and data repository. Ideas were solicited by members of the SPLIT Research Committee and sections were drafted by members of the committee with expertise in those given areas. This review is intended to highlight priorities for clinical research that could successfully be conducted through the SPLIT collaborative and would have significant impact in pediatric liver transplantation.
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Affiliation(s)
- Estella M. Alonso
- Department of Pediatrics; Ann & Robert H. Lurie Children's Hospital of Chicago; Chicago; IL; USA
| | - Vicky L. Ng
- SickKids Transplant Center; The Hospital for Sick Children and University of Toronto; Toronto; ON; Canada
| | | | - Christopher D. Anderson
- Division of Transplant and Hepatobiliary Surgery; University of Mississippi Medical Center; Jackson; MS; USA
| | - Udeme D. Ekong
- Department of Pediatrics; Ann & Robert H. Lurie Children's Hospital of Chicago; Chicago; IL; USA
| | - Emily M. Fredericks
- Division of Child Behavioral Health; Department of Pediatrics and Communicable Diseases; University of Michigan; Ann Arbor; MI; USA
| | - Katryn N. Furuya
- Department of Pediatrics; Thomas Jefferson University; Philadelphia; PA; USA
| | - Nitika A. Gupta
- Department of Pediatrics; Emory University School of Medicine; Atlanta; GA; USA
| | - Stacee M. Lerret
- Department of Pediatrics; Medical College of Wisconsin; Milwaukee; WI; USA
| | - Shikha Sundaram
- Pediatric Liver Center and Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics; University of Colorado Denver School of Medicine; Children's Hospital Colorado; Denver; CO; USA
| | - Greg Tiao
- Departments of Pediatric and Thoracic Surgery; Cincinnati Children's Hospital and Medical Center; Cincinnati; OH; USA
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Semeraro M, Branchereau S, Maibach R, Zsiros J, Casanova M, Brock P, Domerg C, Aronson D, Zimmermann A, Laithier V, Childs M, Roebuck D, Perilongo G, Czauderna P, Brugieres L. Relapses in hepatoblastoma patients: Clinical characteristics and outcome – Experience of the International Childhood Liver Tumour Strategy Group (SIOPEL). Eur J Cancer 2013; 49:915-22. [DOI: 10.1016/j.ejca.2012.10.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Revised: 08/07/2012] [Accepted: 10/01/2012] [Indexed: 10/27/2022]
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Abstract
PURPOSE The proto-oncogene beta-catenin is linked to an abnormal activation of the Wnt/beta-catenin-pathway and shows mutations in 50-90 % of hepatoblastoma (HB). Corresponding, the recently published murine orthotopic HB model differs from the former subcutaneous model by nuclear beta-catenin distribution. As the nuclear localization of beta-catenin is considered to reflect a more aggressive tumor growth, the influence of beta-catenin inhibition on cell viability and drug-efficiency in HB cells was analyzed. METHODS Beta-catenin distribution in HB cells was analyzed by immunofluorescence. The influence of beta-catenin inhibitors Celecoxib, Etodolac, ICG001, and MET kinase inhibitor (SU11274) alone and in combination with cisplatin (CDDP) on HB cell lines (HuH6, HepT1) was evaluated by cell viability assays and BrdU incorporation. RESULTS Celecoxib and ICG001 reduced dose-dependently HB cell viability and decreased nuclear beta-catenin in cultivated HB cells. Etodolac was without influence at concentrations up to 100 μM. Combinations of Celecoxib or ICG001 with MET kinase inhibitor or CDDP resulted in additive reduction of cell viability. CONCLUSION Pharmaceutical beta-catenin inhibitors can modulate the nuclear localization of beta-catenin and reduce cell viability of HB cells in vitro. These promising effects might optimize the outcome of high-risk HB. The orthotopic HB model is a suitable basis for further in vivo studies.
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Vera-Ramirez L, Pérez-Lopez P, Varela-Lopez A, Ramirez-Tortosa M, Battino M, Quiles JL. Curcumin and liver disease. Biofactors 2013; 39:88-100. [PMID: 23303639 DOI: 10.1002/biof.1057] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 09/13/2012] [Indexed: 12/12/2022]
Abstract
Liver diseases pose a major medical problem worldwide and a wide variety of herbs have been studied for the management of liver-related diseases. In this respect, curcumin has long been used in traditional medicine, and in recent years it has been the object of increasing research interest. In combating liver diseases, it seems clear that curcumin exerts a hypolipidic effect, which prevents the fatty acid accumulation in the hepatocytes that may result from metabolic imbalances, and which may cause nonalcoholic steatohepatitis. Another crucial protective activity of curcumin, not only in the context of chronic liver diseases but also regarding carcinogenesis and other age-related processes, is its potent antioxidant activity, which affects multiple processes and signaling pathways. The effects of curcumin on NF-κβ are crucial to our understanding of the potent hepatoprotective role of this herb-derived micronutrient. Because curcumin is a micronutrient that is closely related to cellular redox balance, its properties and activity give rise to a series of molecular reactions that in every case and biological situation affect the mitochondria.
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Affiliation(s)
- Laura Vera-Ramirez
- GENyO Center Pfizer-University of Granada & Andalusian Government Centre for Genomics & Oncology, Granada, Spain
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Lee CT, Zhang L, Mounajjed T, Wu TT. High mobility group AT-hook 2 is overexpressed in hepatoblastoma. Hum Pathol 2012; 44:802-10. [PMID: 23134771 DOI: 10.1016/j.humpath.2012.08.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2012] [Revised: 07/29/2012] [Accepted: 08/05/2012] [Indexed: 11/30/2022]
Abstract
Hepatoblastoma is the most frequent malignant hepatic tumor in children. Expression of high mobility group AT-hook 2, an architectural nuclear factor and marker for hepatic progenitor cells, has not been studied in detail in hepatocellular neoplasms. Immunohistochemical stains using antibodies against high mobility group AT-hook 2, β-catenin, glypican-3, p53, and Ki-67 were performed in 15 hepatoblastomas, 15 fibrolamellar hepatocellular carcinomas, 34 hepatocellular carcinomas (12, ≤30 years old; 22, >30 years old), and 22 hepatic adenomas. High mobility group AT-hook 2 was expressed in all 15 hepatoblastomas, including all fetal and embryonal components, significantly higher than in 41.7% (5/12) of hepatocellular carcinomas of 30 years or younger (P = .001) and in 9% (2/22) of hepatocellular carcinomas of older than 30 years (P < .001). Aberrant β-catenin expression was detected in 80% (12/15) of hepatoblastomas, 41.6% (5/12) of hepatocellular carcinomas of 30 years or younger, and 18.2% (4/22) of hepatocellular carcinomas of older than 30 years. All 15 fibrolamellar hepatocellular carcinomas and 22 hepatic adenomas were negative for high mobility group AT-hook 2 or β-catenin. High mobility group AT-hook 2 and β-catenin expression correlated positively (P = .017; τ = 0.522) in 34 hepatocellular carcinomas. β-Catenin and glypican-3 exhibited a distinct spatial distribution within hepatoblastomas; glypican-3 was more frequently expressed in fetal components (P = .007), whereas β-catenin tended to be more frequently expressed in embryonal components (P = .062). In conclusion, high mobility group AT-hook 2 is expressed in all hepatoblastomas and could be used as a sensitive marker in their diagnosis. High mobility group AT-hook 2 was also expressed in a subset of hepatocellular carcinomas in association with β-catenin expression; this might represent a subtype of hepatocellular carcinoma with hepatic progenitor cell differentiation.
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Affiliation(s)
- Chung-Ta Lee
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan, Republic of China
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López-Terrada D, Zimmermann A. Current issues and controversies in the classification of pediatric hepatocellular tumors. Pediatr Blood Cancer 2012; 59:780-4. [PMID: 22648938 DOI: 10.1002/pbc.24214] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Accepted: 05/08/2012] [Indexed: 02/03/2023]
Abstract
Systematic histopathologic examination of hepatoblastoma specimens from patients enrolled in therapeutic protocols has allowed the identification of clinically relevant histologic subtypes that are being incorporated into risk stratification systems. Genetic and molecular studies have documented recurrent chromosomal abnormalities and aberrant activation of developmental, and oncogenic signaling pathways in hepatoblastoma. Molecular profiling has also identified molecular subclasses and gene signatures that could be used to stratify hepatoblastoma patients. Future international collaboration is needed to develop consensus pathology classifications, and to progressively incorporate genetic and molecular biomarkers into therapeutic pediatric liver tumors protocols.
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Affiliation(s)
- Dolores López-Terrada
- Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA.
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37
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Purcell R, Childs M, Maibach R, Miles C, Turner C, Zimmermann A, Czauderna P, Sullivan M. Potential biomarkers for hepatoblastoma: Results from the SIOPEL-3 study. Eur J Cancer 2012; 48:1853-9. [DOI: 10.1016/j.ejca.2011.10.019] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Revised: 07/13/2011] [Accepted: 10/14/2011] [Indexed: 01/18/2023]
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Pediatric malignancies: neuroblastoma, Wilm's tumor, hepatoblastoma, rhabdomyosarcoma, and sacroccygeal teratoma. Surg Clin North Am 2012; 92:745-67, x. [PMID: 22595719 DOI: 10.1016/j.suc.2012.03.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Common pediatric malignancies are reviewed: neuroblastoma, Wilms tumor, hepatoblastoma, rhabdomyosarcoma, and sacrococcygeal teratoma. Elements of presentation, diagnosis, staging, treatment, and longterm prognosis are discussed, with particular attention to surgical management.
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Herencia C, Martínez-Moreno JM, Herrera C, Corrales F, Santiago-Mora R, Espejo I, Barco M, Almadén Y, de la Mata M, Rodríguez-Ariza A, Muñoz-Castañeda JR. Nuclear translocation of β-catenin during mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotype. PLoS One 2012; 7:e34656. [PMID: 22506042 PMCID: PMC3323576 DOI: 10.1371/journal.pone.0034656] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2011] [Accepted: 03/07/2012] [Indexed: 12/12/2022] Open
Abstract
Wnt/β-catenin pathway controls biochemical processes related to cell differentiation. In committed cells the alteration of this pathway has been associated with tumors as hepatocellular carcinoma or hepatoblastoma. The present study evaluated the role of Wnt/β-catenin activation during human mesenchymal stem cells differentiation into hepatocytes. The differentiation to hepatocytes was achieved by the addition of two different conditioned media. In one of them, β-catenin nuclear translocation, up-regulation of genes related to the Wnt/β-catenin pathway, such as Lrp5 and Fzd3, as well as the oncogenes c-myc and p53 were observed. While in the other protocol there was a Wnt/β-catenin inactivation. Hepatocytes with nuclear translocation of β-catenin also had abnormal cellular proliferation, and expressed membrane proteins involved in hepatocellular carcinoma, metastatic behavior and cancer stem cells. Further, these cells had also increased auto-renewal capability as shown in spheroids formation assay. Comparison of both differentiation protocols by 2D-DIGE proteomic analysis revealed differential expression of 11 proteins with altered expression in hepatocellular carcinoma. Cathepsin B and D, adenine phosphoribosyltransferase, triosephosphate isomerase, inorganic pyrophosphatase, peptidyl-prolyl cis-trans isomerase A or lactate dehydrogenase β-chain were up-regulated only with the protocol associated with Wnt signaling activation while other proteins involved in tumor suppression, such as transgelin or tropomyosin β-chain were down-regulated in this protocol. In conclusion, our results suggest that activation of the Wnt/β-catenin pathway during human mesenchymal stem cells differentiation into hepatocytes is associated with a tumoral phenotype.
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Affiliation(s)
- Carmen Herencia
- Maimónides Institute for Biomedical Research (IMIBIC)/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain
| | - Julio M. Martínez-Moreno
- Maimónides Institute for Biomedical Research (IMIBIC)/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain
| | - Concepción Herrera
- Cellular Therapy Unit, IMIBIC/Reina Sofia University Hospital, Córdoba, Spain
| | - Fernando Corrales
- Center for Applied Medical Research, University of Navarra, Proteomics Laboratory, Pamplona, Spain
| | | | - Isabel Espejo
- Service of Clinic Analysis, Reina Sofía University Hospital, Córdoba, Spain
| | - Monserrat Barco
- Service of Clinic Analysis, Reina Sofía University Hospital, Córdoba, Spain
| | - Yolanda Almadén
- Maimónides Institute for Biomedical Research (IMIBIC)/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain
| | - Manuel de la Mata
- Liver Research Unit, CIBERehd, IMIBIC/Reina Sofia University Hospital, Córdoba, Spain
| | - Antonio Rodríguez-Ariza
- Maimónides Institute for Biomedical Research (IMIBIC)/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain
| | - Juan R. Muñoz-Castañeda
- Maimónides Institute for Biomedical Research (IMIBIC)/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain
- * E-mail:
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Abstract
Tumours and pseudotumours of the liver are a heterogeneous group of neoplasm including 60% of malignant tumours. Malignant liver tumours account for less than 2% of the lesions in children and vary considerably in incidence throughout the paediatric age range, with hepatoblastoma, rhabdoid tumour of the liver, hemangioendothelioma, biliary tract rhabdomysosarcoma and mesenchymal hamartoma in the first two years of life and hepatocellular carcinoma, focal nodular hyperplasia, and undifferentiated sarcoma in older children and adolescents. Treatment of malignant epithelial tumours is based on the surgical resection of the tumour associated with pre- and postoperative chemotherapy including cisplatinum. Modalities of the treatment are adapted to risk factors. Survival rates at three years are over 80% for localised hepatoblastoma whereas they are less than 30% in hepatocellular carcinomas. The role of targeted therapies still has to be defined.
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Abstract
Hepatoblastoma is the most common liver tumor of early childhood. According to recent studies its incidence seems to be increasing in North America and Europe. Since new histological variants have been described recently the formerly clear-cut distinction of hepatoblastoma and hepatocellular carcinoma may not be valid anymore and a new histological classification will be inaugurated by an international working group. Recent research identified prognostically relevant gene signatures as well as potential molecular targets for therapy of hepatoblastoma. The multicentric study groups in the USA, Europe and Japan recommend cisplatin based chemotherapy for neoadjuvant and adjuvant treatment. However, their risk stratification systems and general treatment strategies differ substantially. Therefore the four groups agreed to pool their patients' data for an analysis of prognostic criteria which can be used for defining common risk groups. While 90% of standard risk and 65% of high risk hepatoblastomas can be cured, the still dismal outcome of multifocal disseminated and metastasising tumors warrants the investigation of new cytotoxic drugs and substances against specific molecular targets.
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Tsay PK, Lai JY, Yang CP, Hung IJ, Hsueh C, Tsai MH, Jaing TH. Treatment outcomes for hepatoblastoma: experience of 35 cases at a single institution. J Formos Med Assoc 2011; 110:322-5. [PMID: 21621153 DOI: 10.1016/s0929-6646(11)60048-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2010] [Revised: 05/29/2010] [Accepted: 05/31/2010] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND/PURPOSE Hepatoblastoma is the most common malignant liver tumor in children. Comparative studies have elucidated the optimal pre- or postoperative chemotherapeutic regimens. The aim of this study was to investigate the prognostic significance of baseline tumor characteristics for overall survival and disease-free survival in children with hepatoblastoma. METHODS There were 19 male and 16 female children with a median age of 19 months at diagnosis (range: 1-169 months) in our institution between February 1990 and June 2009. We reviewed the clinical presentation, serum α-fetoprotein level at diagnosis, histological subtype, treatment, and outcomes. RESULTS Twenty-seven patients (78%) underwent neoadjuvant chemotherapy. The majority of patients subsequently underwent either hemihepatectomy (56%) or bisegmentectomy (16%). Only six patients underwent extended hepatic resection, and one of them required rescue liver transplantation. During follow-up, six patients died of progressive disease and two of perioperative mortality. Four of the six who died had pulmonary metastases at the time of diagnosis or follow-up. The median survival time was 28 months (range: 1-181 months). Five-year overall survival was 67.7% (95% confidence interval: 52.0-87.8%) and disease-free survival was 60.2% (95% confidence interval: 41.9-86.5%). CONCLUSION The potential down-staging effect of neoadjuvant chemotherapy on hepatoblastoma might facilitate remission and convert unresectable tumors into operable ones.
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Affiliation(s)
- Pei-Kwei Tsay
- Department of Public Health and Center of Biostatistics, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Purcell R, Childs M, Maibach R, Miles C, Turner C, Zimmermann A, Sullivan M. HGF/c-Met related activation of β-catenin in hepatoblastoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2011; 30:96. [PMID: 21992464 PMCID: PMC3207961 DOI: 10.1186/1756-9966-30-96] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2011] [Accepted: 10/12/2011] [Indexed: 02/08/2023]
Abstract
Background Activation of beta-catenin is a hallmark of hepatoblastoma (HB) and appears to play a crucial role in its pathogenesis. While aberrant accumulation of the beta-catenin is a common event in HB, mutations or deletions in CTNNB1 (beta-catenin gene) do not always account for the high frequency of protein expression. In this study we have investigated alternative activation of beta-catenin by HGF/c-Met signaling in a large cohort of 98 HB patients enrolled in the SIOPEL-3 clinical trial. Methods We performed immunohistochemistry, using antibodies to total beta-catenin and tyrosine654-phosphorylated beta-catenin, which is a good surrogate marker of HGF/c-Met activation. CTNNB1 mutation analysis was also carried out on all samples. We also investigated beta-catenin pathway activation in two liver cancer cell lines, HuH-6 and HuH-7. Results Aberrant beta-catenin expression was seen in the cytoplasm and/or nucleus of 87% of tumour samples. Our results also revealed a large subset of HB, 83%, with cytoplasmic expression of tyrosine654-phosphorylated beta-catenin and 30% showing additional nuclear accumulation. Sequence analysis revealed mutations in 15% of our cohort. Statistical analysis showed an association between nuclear expression of c-Met-activated beta-catenin and wild type CTNNB1 (P-value = 0.015). Analysis of total beta-catenin and Y654-beta-catenin in response to HGF activation in the cell lines, mirrors that observed in our HB tumour cohort. Results We identified a significant subset of hepatoblastoma patients for whom targeting of the c-Met pathway may be a treatment option and also demonstrate distinct mechanisms of beta-catenin activation in HB.
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Affiliation(s)
- Rachel Purcell
- Children's Cancer Research Group, University of Otago, Christchurch, Christchurch, New Zealand.
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44
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Over-expression of SERPINB3 in hepatoblastoma: a possible insight into the genesis of this tumour? Eur J Cancer 2011; 48:1219-26. [PMID: 21737255 DOI: 10.1016/j.ejca.2011.06.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2011] [Revised: 05/12/2011] [Accepted: 06/03/2011] [Indexed: 12/22/2022]
Abstract
BACKGROUND The serpin SERPINB3 (SB3) found over-expressed in human hepatocellular carcinoma and in regenerating liver in mice has been shown to induce apoptosis resistance, epithelial-to-mesenchymal transition and increasing cellular invasion. It has also been hypothesised that SB3 may provide a pro-proliferative stimulus for liver cells in vivo. No information is available on SB3 in hepatoblastoma (HB). Aims of the study were to analyse SB3 expression in HB specimens and to investigate its possible correlation with Myc expression and tumour extension at diagnosis as evaluated by the pre-treatment extent of disease evaluation system (PRETEXT). METHODS Frozen tumour specimens from 42 children with HB were analysed for SB3 and Myc expression by real-time PCR. SB3 localisation in tumour specimens was assessed by immunohistochemistry. RESULTS At transcription level SB3 was positive in 79% of the cases. By immunohistochemistry, SB3 expression was found mainly in the embryonic, blastemal, small cell undifferentiated (SCUD) components of HB, while it was not detectable in normal hepatocytes. High SB3 reactivity was also detected in neoplastic cell clusters of portal vein tumour thrombosis. A direct correlation was observed between SB3 gene expression, the up-regulation of Myc (r=0.598, p<0.0001) and tumour extension (PRETEXT III/IV versus I/II, p=0.013). CONCLUSIONS SB3 is over-expressed in HB and its expression is positively correlated with Myc expression and high tumour stage. The role of SB3 in the genesis of HB and in defining the risk profile of children affected by this tumour is hypothesised.
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46
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Abstract
The Wnt signaling pathway is an evolutionarily conserved, highly complex signaling pathway that is critical for development, differentiation and cellular homeostasis. The protein β-catenin is the central player in one major arm of the Wnt pathway called the canonical Wnt pathway. As in other organs, the Wnt/β-catenin pathway is critical for liver development. However, recent research suggests that the pathway is also important in liver regeneration, liver metabolism and maintenance of normal function in the adult liver. Aberrant activation of β-catenin has also been implicated in the pathogenesis of hepatobiliary neoplasia, ranging from benign lesions to liver cancer. The explosion of research into the many roles of the Wnt/β-catenin pathway promises to change our fundamental understanding of normal liver biology and the aberrations that lead to disease and cancer.
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Affiliation(s)
- Jaideep Behari
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Suite 916 Kaufmann Medical Building, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA.
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Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer. Proc Natl Acad Sci U S A 2010; 107:20471-6. [PMID: 21059911 DOI: 10.1073/pnas.1009009107] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Myc activation has been implicated in the pathogenesis of hepatoblastoma (HB), a rare embryonal neoplasm derived from liver progenitor cells. Here, microRNA (miR) expression profiling of 65 HBs evidenced differential patterns related to developmental stage and Myc activity. Undifferentiated aggressive HBs overexpressed the miR-371-3 cluster with concomitant down-regulation of the miR-100/let-7a-2/miR-125b-1 cluster, evoking an ES cell expression profile. ChIP and Myc inhibition assays in hepatoma cells demonstrated that both miR clusters are regulated by Myc in an opposite manner. We show that the two miR clusters exert antagonistic effects on cell proliferation and tumorigenicity. Moreover, their combined deregulation cooperated in modulating the hepatic tumor phenotype, implicating stem cell-like regulation of Myc-dependent miRs in poorly differentiated HBs. Importantly, a four-miR signature representative of these clusters efficiently stratified HB patients, and when applied to 241 hepatocellular carcinomas (HCCs), it identified invasive tumors with a poor prognosis. Our data argue that Myc-driven reprogramming of miR expression patterns contributes to the aggressive phenotype of liver tumors originating from hepatic progenitor cells.
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48
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Grossman EJ, Millis JM. Liver transplantation for non-hepatocellular carcinoma malignancy: Indications, limitations, and analysis of the current literature. Liver Transpl 2010; 16:930-42. [PMID: 20677284 DOI: 10.1002/lt.22106] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Orthotopic liver transplantation (OLT) is currently incorporated into the treatment regimens for specific nonhepatocellular malignancies. For patients suffering from early-stage, unresectable hilar cholangiocarcinoma (CCA), OLT preceded by neoadjuvant radiotherapy has the potential to readily achieve a tumor-free margin, accomplish a radical resection, and treat underlying primary sclerosing cholangitis when present. In highly selected stage I and II patients with CCA, the 5-year survival rate is 80%. As additional data are accrued, OLT with neoadjuvant chemoradiation may become a viable alternative to resection for patients with localized, node-negative hilar CCA. Hepatic involvement from neuroendocrine tumors can be treated with OLT when metastases are unresectable or for palliation of medically uncontrollable symptoms. Five-year survival rates as high as 90% have been reported, and the Ki67 labeling index can be used to predict outcomes after OLT. Hepatic epithelioid hemangioendothelioma is a rare tumor of vascular origin. The data from single-institution series are limited, but compiled reviews have reported 1- and 10-year survival rates of 96% and 72%, respectively. Hepatoblastoma is the most common primary hepatic malignancy in children. There exist subtle differences in the timing of chemotherapy between US and European centers; however, the long-term survival rate after transplantation ranges from 66% to 77%. Fibrolamellar hepatocellular carcinoma is a distinct liver malignancy best treated by surgical resection. However, there is an increasing amount of data supporting OLT when resection is contraindicated. In the treatment of either primary or metastatic hepatic sarcomas, unacceptable survival and recurrence rates currently prohibit the use of OLT.
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Affiliation(s)
- Eric J Grossman
- Section of Transplantation, Department of Surgery, University of Chicago Medical Center, Chicago, IL 60637, USA
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49
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Pryce J, Kiho L, Scheimberg I. Sudden unexpected death in infancy associated with an epithelial-type hepatoblastoma in a 6-month-old infant. Pediatr Dev Pathol 2010; 13:338-40. [PMID: 20170276 DOI: 10.2350/09-07-0687-cr.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Sudden unexpected death in infancy and childhood attributable to undiagnosed neoplasia is rare. Malignant neoplasms are very uncommon in infancy, with an age-standardized incidence rate of 118.3 per million. Primary malignant liver tumors are rare, with hepatoblastoma accounting for up to two thirds of cases. Although hepatoblastoma is the most common malignant neoplasm of the liver in childhood, it only accounts for 3.1% of childhood cancers for infants less than 12 months of age. We describe the first case of sudden death in an apparently healthy 6-month-old infant whose autopsy revealed an epithelial type hepatoblastoma with mixed fetal and embryonal patterns.
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Affiliation(s)
- Jeremy Pryce
- Department of Cellular Pathology, The Royal London Hospital, Barts and The London NHS Trust, Pathology and Pharmacy Building, 80 Newark Street, London E1 2ES, UK
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50
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Grunewald TGP, von Luettichau I, Welsch U, Dörr HG, Höpner F, Kovacs K, Burdach S, Rabl W. First report of ectopic ACTH syndrome and PTHrP-induced hypercalcemia due to a hepatoblastoma in a child. Eur J Endocrinol 2010; 162:813-8. [PMID: 20133447 DOI: 10.1530/eje-09-0961] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
CONTEXT Only occasionally, endocrine-active tumors develop directly from hepatic tissue, and may lead to paraneoplastic syndromes (PNS). PNS mostly accompany malignancy of adulthood and are exceedingly rare in children. PATIENT A girl aged 6 years and 9 months presented with a 2-month history of rapidly progressive weight gain, abdominal distension, and polyuria/pollakiuria accompanied by short episodes of abdominal pain. She showed the typical clinical features of Cushing's syndrome and a huge hepatic mass. An abdominal computed tomography (CT) scan revealed a large liver tumor. Blood glucose and serum calcium were greatly elevated. DESIGN AND OBJECTIVE Case report describing the causative relationship of the clinical findings. METHODS Physical examination; ultrasound of the abdomen; CT scan of the abdomen and the chest; conventional X-rays; routine hematology; blood chemistry and multiple parameters of calcium and phosphorus metabolism; multisteroid analysis in serum and urine; adrenocortical stimulation and suppression tests; histopathological assessment of the resected tumor; immunohistochemistry for ACTH, beta-endorphin, corticotrophin-releasing hormone (CRH), and PTH-related peptide (PTHrP); electron microscopy of tumor cells; ACTH and CRH extraction from the tumor tissue; and clinical follow-up for more than 20 years. RESULTS Giant hepatoblastoma (HB; approximately 1000 ml volume) of the right lobe of the liver with combined ectopic ACTH syndrome and PTHrP-induced tumor-associated hypercalcemia. Wide local excision and polychemotherapy led to complete reversal of the paraneoplastic phenotype. CONCLUSIONS This is the first report of an endocrine-active HB causing both Cushing's syndrome and PTHrP-related 'humoral hypercalcemia of malignancy'. This information should be added to the well-known beta-human chorionic gonadotropin-related paraneoplastic effects of HB in children.
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Affiliation(s)
- Thomas G P Grunewald
- Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Kölner Platz 1, D-80804 Munich, Germany
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