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      Mouse models of liver cancer: Progress and recommendations

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          Abstract

          To clarify the pathogenesis of hepatocellular carcinoma (HCC) and investigate the effects of potential therapies, a number of mouse models have been developed. Subcutaneous xenograft models are widely used in the past decades. Yet, with the advent of in vivo imaging technology, investigators are more and more concerned with the orthotopic models nowadays. Genetically engineered mouse models (GEM) have greatly facilitated studies of gene function in HCC development. Recently, GEM of miR-122 and miR-221 provided new approaches for better understanding of the in vivo functions of microRNA in hepatocarcinogenesis. Chemically induced liver tumors in animals share many of the morphological, histogenic, and biochemical features of human HCC. Yet, the complicated and obscure genomic alternation restricts their applications. In this review, we highlight both the frequently used mouse models and some emerging ones with emphasis on their merits or defects, and give advises for investigators to chose a “best-fit” animal model in HCC research.

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          Most cited references124

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          Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver.

          miR-122, an abundant liver-specific microRNA (miRNA), regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication. Reduced miR-122 expression in hepatocellular carcinoma (HCC) correlates with metastasis and poor prognosis. Nevertheless, the consequences of sustained loss of function of miR-122 in vivo have not been determined. Here, we demonstrate that deletion of mouse Mir122 resulted in hepatosteatosis, hepatitis, and the development of tumors resembling HCC. These pathologic manifestations were associated with hyperactivity of oncogenic pathways and hepatic infiltration of inflammatory cells that produce pro-tumorigenic cytokines, including IL-6 and TNF. Moreover, delivery of miR-122 to a MYC-driven mouse model of HCC strongly inhibited tumorigenesis, further supporting the tumor suppressor activity of this miRNA. These findings reveal critical functions for miR-122 in the maintenance of liver homeostasis and have important therapeutic implications, including the potential utility of miR-122 delivery for selected patients with HCC and the need for careful monitoring of patients receiving miR-122 inhibition therapy for HCV.
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            MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer.

            Hepatocellular carcinoma is generally refractory to clinical treatment. Here, we report that inactivation of the MYC oncogene is sufficient to induce sustained regression of invasive liver cancers. MYC inactivation resulted en masse in tumour cells differentiating into hepatocytes and biliary cells forming bile duct structures, and this was associated with rapid loss of expression of the tumour marker alpha-fetoprotein, the increase in expression of liver cell markers cytokeratin 8 and carcinoembryonic antigen, and in some cells the liver stem cell marker cytokeratin 19. Using in vivo bioluminescence imaging we found that many of these tumour cells remained dormant as long as MYC remain inactivated; however, MYC reactivation immediately restored their neoplastic features. Using array comparative genomic hybridization we confirmed that these dormant liver cells and the restored tumour retained the identical molecular signature and hence were clonally derived from the tumour cells. Our results show how oncogene inactivation may reverse tumorigenesis in the most clinically difficult cancers. Oncogene inactivation uncovers the pluripotent capacity of tumours to differentiate into normal cellular lineages and tissue structures, while retaining their latent potential to become cancerous, and hence existing in a state of tumour dormancy.
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              PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells.

              In normal brain, the side population (SP) phenotype is generated by ABC transporter activity and identifies stem cell and endothelial cell subpopulations by dye exclusion. By drug efflux, the ABCG2 transporter provides chemoresistance in stem cells and contributes to the blood brain barrier (BBB) when active in endothelial cells. We investigated the SP phenotype of mouse and human gliomas. In glioma endothelial cells, ABC transporter function is impaired, corresponding to disruption of the BBB in these tumors. By contrast, the SP phenotype is increased in nonendothelial cells that form neurospheres and are highly tumorigenic. In this cell population, Akt, but not its downstream target mTOR, regulates ABCG2 activity, and loss of PTEN increases the SP. This Akt-induced ABCG2 activation results from its transport to the plasma membrane. Temozolomide, the standard treatment of gliomas, although not an ABCG2 substrate, increases the SP in glioma cells, especially in cells missing PTEN.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                15 September 2015
                5 June 2015
                : 6
                : 27
                : 23306-23322
                Affiliations
                1 Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
                Author notes
                Correspondence to: Xing-Xing He, xxhe@ 123456tjh.tjmu.edu.cn
                Article
                10.18632/oncotarget.4202
                4695120
                26259234
                e776a6f7-ecd9-45d0-87e5-7a42a54784f0
                Copyright: © 2015 He et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 23 March 2015
                : 23 May 2015
                Categories
                Review

                Oncology & Radiotherapy
                hepatocellular carcinoma,animal model,xenograft model,microrna
                Oncology & Radiotherapy
                hepatocellular carcinoma, animal model, xenograft model, microrna

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