A Study of Therapy for Pediatric Hepatoblastoma: Prevention and Treatment of Pulmonary Metastasis

Uchiyama, Makoto; Iwafuchi, Makoto; Naito, Makoto; Yagi, Masayuki; Iinuma, Yasushi; Kanada, Satoshi; Tsukada, K.

doi:10.1055/s-2008-1072230

Cited by 12 publications

(10 citation statements)

References 14 publications

(39 reference statements)

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“…We observed metastases in both the liver and the lung in 50% (three out of six) of the successfully established PDTXs. The metastatic disease we observed is similar to human clinical data, where 46% HB and 44% HCC patients develop metastatic disease, primarily in the lung [33,34]. We also demonstrated that the orthotopic PDTXs preserve tumor heterogeneity not only within the primary xenograft but, intriguingly, also within specific metastases.…”

Section: Discussionsupporting

confidence: 85%

Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer

Bissig-Choisat

Kettlun-Leyton

Legras

et al. 2016

Journal of Hepatology

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Background & Aims Pediatric liver cancer is a rare but serious disease whose incidence is rising, and for which the therapeutic options are limited. Development of more targeted, less toxic therapies is hindered by the lack of an experimental animal model that captures the heterogeneity and metastatic capability of these tumors. Methods Here we established an orthotopic engraftment technique to model a series of patient-derived tumor xenograft (PDTX) from pediatric liver cancers of all major histologic subtypes: hepatoblastoma, hepatocellular cancer and hepatocellular malignant neoplasm. We utilized standard (immuno) staining methods for histological characterization, RNA sequencing for gene expression profiling and genome sequencing for identification of druggable targets. We also adapted stem cell culturing techniques to derive two new pediatric cancer cell lines from the xenografted mice. Results The patient-derived tumor xenografts recapitulated the histologic, genetic, and biological characteristics—including the metastatic behavior—of the corresponding primary tumors. Furthermore, the gene expression profiles of the two new liver cancer cell lines closely resemble those of the primary tumors. Targeted therapy of PDTX from an aggressive hepatocellular malignant neoplasm with the MEK1 inhibitor trametinib and pan-class I PI3 kinase inhibitor NVP-BKM120 resulted in significant growth inhibition, thus confirming this PDTX model as a valuable tool to study tumor biology and patient-specific therapeutic responses. Conclusions The novel metastatic xenograft model and the isogenic xenograft-derived cell lines described in this study provide reliable tools for developing mutation- and patient-specific therapies for pediatric liver cancer. Lay summary Pediatric liver cancer is a rare but serious disease and no experimental animalmodel currently captures the complexity and metastatic capability of these tumors. We have established a novel animal model using human tumor tissue that recapitulates the genetic and biological characteristics of this cancer. We demonstrate that our patient-derived animal model, as well as two new cell lines, are useful tools for experimental therapies.

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Section: Discussionsupporting

confidence: 85%

Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer

Bissig-Choisat

Kettlun-Leyton

Legras

et al. 2016

Journal of Hepatology

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“…46% and 44% of human HCC and HB patients, respectively, have metastatic disease, primarily in the lung (38, 39). As was the case for the primary Tg-β-cat S tumors, we observed robust β-catenin expression in a lung metastasis.…”

Section: Discussionmentioning

confidence: 99%

β-Catenin Activation in a Novel Liver Progenitor Cell Type Is Sufficient to Cause Hepatocellular Carcinoma and Hepatoblastoma

et al. 2014

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Hepatocellular carcinoma (HCC) was thought historically to arise from hepatocytes, but gene expression studies have suggested 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™-GFP BAC transgene in which a tamoxifen-inducible Cre (CreER™) and GFP are controlled by a 190kb 5′ genomic region of Cited1, a transcriptional co-activator 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™-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, >90% of Cited1-CreER™-GFP; Ctnnb1ex3(fl) mice with Wnt pathway activation developed HCC and, in some cases, hepatoblastomas (HB) and lung metastases. HCC and HB 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 HB and the development of improved therapeutics for these diseases.

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“…While early case reports showed the potential for cure following metastasectomy, initial chemotherapy trials also showed the possibility of complete resolution of lung metastases with chemotherapy alone. Two larger Japanese trials showed the importance of this combined approach and emphasized the use of metastasectomy for residual lung disease after chemotherapy 65, 66 . The strategy of combining chemotherapy and metastasectomy for residual disease is still used in all major hepatoblastoma cooperative trials for patients with pulmonary metastatic disease at diagnosis.…”

Section: Hepatoblastomamentioning

confidence: 99%

Surgical treatment of pulmonary metastases in pediatric solid tumors

Heaton

Davidoff

2016

Seminars in Pediatric Surgery

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Most children who succumb to solid malignancies do so because of the burden of metastatic disease or due to complications associated with the therapy administered to treat metastatic disease. Approximately one-quarter of children with solid tumors will present with metastatic disease, and an additional 20% ultimately develop metastatic disease, most commonly in the lung. The role of surgery in the treatment of metastatic solid tumors, given its disseminated nature, is not intuitive, yet there are circumstances in which surgical resection of metastatic disease can potentially be curative. However, the utility of surgery is very much dependent on histology, and generally is most appropriate for those malignancies with histologies that are refractory to other adjuvant therapies.

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A Study of Therapy for Pediatric Hepatoblastoma: Prevention and Treatment of Pulmonary Metastasis

Cited by 12 publications

References 14 publications

Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer

Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer

β-Catenin Activation in a Novel Liver Progenitor Cell Type Is Sufficient to Cause Hepatocellular Carcinoma and Hepatoblastoma

Surgical treatment of pulmonary metastases in pediatric solid tumors

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