Dual functions of E2F-1 in a transgenic mouse model of liver carcinogenesis

Conner, Elizabeth A.; Lemmer, Eric R.; Omori, Masako; Wirth, Peter J.; Factor, Valentina M.; Thorgeirsson, Snorri S.

doi:10.1038/sj.onc.1203885

Cited by 138 publications

(130 citation statements)

References 46 publications

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“…27 In our study, the expression of the GFP transgene was stable and did not decrease during ES cell growth, as reported previously. 28,29 To induce hepatic differentiation, we used the developmental potential of the ES/EB system to mimic hepatogenesis in the early embryo. 1 Consistent with the inductive role of cardiac mesoderm in hepatic differentiation, 30 the first GFP ϩ cells that displayed morphologic characteristics and expressed hepatocyte-specific markers were found in close proximity to contracting cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver

et al. 2006

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We established an efficient system for differentiation, expansion and isolation of hepatic progenitor cells from mouse embryonic stem (ES) cells and evaluated their capacity to repopulate injured liver. Using mouse ES cells transfected with the green fluorescent protein (GFP) reporter gene regulated by albumin (ALB) enhancer/promoter, we found that a serum-free chemically defined medium supports formation of embryoid bodies (EBs) and differentiation of hepatic lineage cells in the absence of exogenous growth factors or feeder cell layers. The first GFP ؉ cells expressing ALB were detected in close proximity to "beating" myocytes after 7 days of EB cultures. GFP ؉ cells increased in number, acquired hepatocyte-like morphology and hepatocytespecific markers (i.e., ALB, AAT, TO, and G6P), and by 28 days represented more than 30% of cells isolated from EB outgrowths. The FACS-purified GFP ؉ cells developed into functional hepatocytes without evidence of cell fusion and participated in the repairing of diseased liver when transplanted into MUP-uPA/SCID mice. The ES cell-derived hepatocytes were responsive to normal growth regulation and proliferated at the same rate as the host hepatocytes after an additional growth stimulus from CCl 4 -induced liver injury. The transplanted GFP ؉ cells also differentiated into biliary epithelial cells. In conclusion, a highly enriched population of committed hepatocyte precursors can be generated from ES cells in vitro for effective cell replacement therapy. Supplementary material for this article can be found on the HEPATOLOGY website H epatocyte transplantation is an effective treatment for liver failure and/or end-stage liver disease. However, the shortage of donor organs and the difficulties of cyropreservation and long-term culturing of mature hepatocytes have limited the clinical application of cell-based therapy. Recently, the use of embryonic stem (ES) cells has attracted considerable interest for cell replacement therapy because of their capacity to proliferate indefinitely in vitro while retaining the potential to differentiate into all types of cells including hepatocytes. [1][2][3][4][5] Clinical application of ES cells requires a simple and efficient protocol for directing their differentiation into a specific cell type. Several studies have reported the induction of ES cell differentiation into hepatocytes both in vitro 6-9 and in vivo. 10 The in vitro approaches involve the formation of embryoid bodies (EBs) to re-create the inductive microenvironment required for liver organogenesis 11,12 or treatment with specific growth factors and cytokines critical for hepatocyte differentiation such as hepatocyte growth factor, fibroblast growth factor, and oncostatin. 1,13 Also, the introduction of genes promoting endodermal differentiation into ES cells, 14 modification of culture microenvironment by supplementation with extracellular matrix proteins or coculture with other cell types, 15,16 is used to direct ES cells toward a hepatocytic lineage. Nevertheless, these strategie...

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Section: Discussionmentioning

confidence: 99%

Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver

et al. 2006

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“…59 However, there are several lines of evidence to support the notion that increased expression of proliferative E2Fs are important for hepatocarcinogenesis. Hepatocyte proliferation is increased in early stages of carcinogenesis in mice in which E2F-1 is overexpressed 60 and in a c-myc/TGF-α double transgenic mouse carcinogenesis model, both E2F-1 and E2F-2 are expressed at increased levels. 61 The earliest cyclin-cdk complex activated during G 1 phase progression is Cyclin D-cdk4/6.…”

Section: Pathways Important For the Regulation Of The G 1 /S Restrictmentioning

confidence: 99%

Cell cycle regulation and hepatocarcinogenesis

Greenbaum¹

2004

Cancer Biology & Therapy

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“…23,24 Double transgenic Alb/ c-myc/Alb/E2F1 (c-Myc/E2F1) mice were generated by crossing homozygous E2F1 (line 8) with homozygous c-Myc (line 166.8) mice. 25 Animal housing and care were in accordance with National Institutes of Health guidelines.…”

Section: Transgenic Micementioning

confidence: 99%

“…[19][20][21][22] We have previously generated a number of transgenic mouse models prone to liver cancer, including c-Myc, E2F1, c-Myc/TGF-a and c-Myc/ E2F1. [23][24][25] These transgenic mice developed HCC with different morphological and biological features. In particular, coexpression of c-Myc with TGF-a or E2F1 resulted in a shorten tumor latency, higher incidence as well as in a more aggressive phenotype when compared with single transgenic lines.…”

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confidence: 99%

“…In particular, coexpression of c-Myc with TGF-a or E2F1 resulted in a shorten tumor latency, higher incidence as well as in a more aggressive phenotype when compared with single transgenic lines. [23][24][25] In order to elucidate the role of E-cadherin in the sequential steps of liver carcinogenesis, we have analyzed the expression patterns of E-cadherin in a collection of preneoplastic and neoplastic liver lesions from c-Myc, E2F1, c-Myc/TGF-a and c-Myc/ E2F1 transgenic mice. In particular, we have investigated the relevance of genetic, epigenetic and transcriptional mechanisms on E-cadherin protein expression levels.…”

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confidence: 99%

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Disregulation of E-cadherin in transgenic mouse models of liver cancer

Calvisi

Ladu

Conner

et al. 2004

Laboratory Investigation

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E-cadherin is a cell-cell adhesion molecule that plays a pivotal role in the development and maintenance of cell polarity. Disruption of E-cadherin-mediated adhesion represents a key step toward the invasive phenotype in a variety of solid tumors, including hepatocellular carcinoma (HCC). Here, we investigate whether deregulation of E-cadherin occurs along the multistep process of hepatocarcinogenesis in transgenic mouse models, including c-Myc, E2F1, c-Myc/TGF-a and c-Myc/E2F1 mice. Liver tumors from the transgenic mouse lines could be divided into two categories based on E-cadherin levels. Of 28, 20 (71.4%) c-Myc HCCs showed marked reduction of E-cadherin expression when compared with wild-type livers. In contrast, all of c-Myc/TGF-a and the majority of E2F1 and c-myc/E2F1 preneoplastic and neoplastic lesions exhibited overexpression of E-cadherin. Downregulation of E-cadherin was associated with promoter hypermethylation in seven of 20 c-Myc HCCs (35%), while no loss of heterozygosity at the E-cadherin locus was detected. Nuclear accumulation of b-catenin did not correlate with E-cadherin downregulation. Furthermore, c-Myc HCCs with reduced E-cadherin displayed upregulation of hypoxia-inducible factor-1a and vascular endothelial growth factor proteins. Importantly, loss of E-cadherin was associated with increased cell proliferation and higher microvessel density in c-Myc tumors. Taken together, these data suggest that loss of E-cadherin might favor tumor progression in relatively more benign HCC from c-Myc transgenic mice by stimulating neoplastic proliferation and angiogenesis under hypoxic conditions.

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Dual functions of E2F-1 in a transgenic mouse model of liver carcinogenesis

Cited by 138 publications

References 46 publications

Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver

Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver

Cell cycle regulation and hepatocarcinogenesis

Disregulation of E-cadherin in transgenic mouse models of liver cancer

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