A transgenic zebrafish liver tumor model with inducible Myc expression reveals conserved Myc signatures with mammalian liver tumors

Percutaneous locoregional therapies (LRTs), such as thermal ablation, are performed to limit the progression of hepatocellular carcinoma (HCC) and offer a bridge for patients waiting for liver transplantation. However, physiological challenges related to tumor location, size, and existence of multiple lesions as well as safety concerns related to potential thermal injury to adjacent tissues may preclude the use of thermal ablation or lead to its failure. Here, we showed a successful injection of an ionic liquid into tissue under image guidance, ablation of tumors in response to the injected ionic liquid, and persistence (28 days) of coinjected chemotherapy with the ionic liquid in the ablation zone. In a rat HCC model, the rabbit VX2 liver tumor model, and 12 human resected tumors, injection of the ionic liquid led to consistent tumor ablation. Combining the ionic liquid with the chemotherapy agent, doxorubicin, resulted in synergistic cytotoxicity when tested with cultured HCC cells and uniform drug distribution throughout the ablation zone when percutaneously injected into liver tumors in the rabbit liver tumor model. Because this ionic liquid preparation is simple to use, is efficacious, and has a low cost, we propose that this new LRT may bridge more patients to liver transplantation.

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PL-019 Effect of early exercise on autophagy of liver tumor in mice

Exercise Biochemistry Review ◽

10.14428/ebr.v1i1.8223 ◽

2018 ◽

Vol 1 (1) ◽

Author(s):

Ning Jiang ◽

Zhe Wang ◽

Jing Li ◽

Xinghao Wang

Keyword(s):

Exercise Training ◽

Liver Tumor ◽

Liver Tumors ◽

Hepatoma Cell ◽

Tumor Model ◽

Inflammatory Cells ◽

Exercise Group ◽

Control Group ◽

Early Exercise ◽

Tumor Group

Objective To investigate whether the liver autophagy level can be altered by pre exercise training in mice liver tumors. Methods 40 Male C57BL/6J mice aged 7 months were randomly divided into 2 groups: control group (YC) and exercise group (YE). YE were exercised on a treadmill for 12 weeks (12m/min). After12 weeks each group was randomly divided into two groups. The tumor model was constructed by injection of HEPA1- 6 mouse hepatoma cell into liver tissue.Then the groups were control group (YC), exercise group (YE), tumor group (YCT), exercise tumor group (YET).The experimental samples were prepared on the 13 day after the tumor model was constructed. the hematoxylin and eosin stain of the liver was observed.The expression of autophagy related protein BECLIN1, LC3-II and ATG5 in liver tissues of mice was detected by Western blot. Results Compared with YCT group,the boundary of inflammatory cells and tumor cells in YET group was clear with normal cells.Compared with YCT group, the expression levels of BECLIN1, LC3-II and ATG5 in liver tissue of YET group were significantly higher (p < 0.01, P < 0.01, P < 0.05). Conclusions Early exercise can help the 7 month old mice to resist the occurrence and development of the liver tumor. It's probably associated with increased level of autophagy in the liver by early exercise training.

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Advancement to the clinic of an RNAi therapeutic for solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.3585 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 3585-3585

Author(s):

D. Bumcrot ◽

I. Toudjarska ◽

A. Judge ◽

J. Brodsky ◽

E. Ambegia ◽

...

Keyword(s):

Solid Tumors ◽

Liver Tumor ◽

Liver Tumors ◽

Tumor Model ◽

Tumor Burden ◽

Systemic Administration ◽

Primary Hepatocellular Carcinoma ◽

Human Hepatoma Cells ◽

Lipid Particle

3585 Background: Malignancies of the liver, including primary (hepatocellular carcinoma) and secondary (metastatic) tumors, represent a significant unmet medical need. We are developing a therapeutic for solid tumors involving the liver that is comprised of lipid particle-formulated short interfering RNAs (siRNAs) targeting VEGF and the mitotic kinesin, KSP (Eg5). For each target, potent siRNA duplexes were selected following extensive screening in tissue culture cells. Efficacy was demonstrated in a mouse liver tumor model. Methods: To assess efficacy in vivo, a stable nucleic acid lipid particle (SNALP) formulation was developed based on similar formulations previously shown to silence liver-expressed genes via systemic administration in multiple species. A SNALP-formulated combination of the KSP and VEGF siRNAs (referred to as ALN-VSP01) was tested in an orthotopic liver tumor model in which human hepatoma cells (Hep3B) are implanted directly into the livers of immunocompromised mice. Results: Intravenous administration of ALN-VSP01 leads to dose-dependent inhibition of both KSP and VEGF expression in established liver tumors. This was accompanied by the formation of numerous aberrant mitotic figures (“monoasters”) in tumor cells indicative of the pharmacologic inhibition of KSP. In addition, tumor growth was significantly inhibited by a course of ALN-VSP01 treatment, and ALN-VSP01 treatment provided a clear survival benefit even when treatment was initiated in animals with a significant tumor burden. As a control, a SNALP-formulated siRNA targeting Luciferase was administered and shown to have no effect in these studies. Conclusions: Systemic administration of ALN-VSP01 exhibited clear efficacy in a mouse orthotopic liver tumor model. Clinical testing of ALN-VSP01 is expected to initiate in early 2009. [Table: see text]

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Exacerbation of Liver Tumor Metastasis in twist1a+/xmrk+ Double Transgenic Zebrafish Following Lipopolysaccharide or Dextran Sulphate Sodium Exposure

Pharmaceuticals ◽

10.3390/ph14090867 ◽

2021 ◽

Vol 14 (9) ◽

pp. 867

Author(s):

Jeng-Wei Lu ◽

Yuxi Sun ◽

Liang-In Lin ◽

Dong Liu ◽

Zhiyuan Gong

Keyword(s):

Liver Tumor ◽

Tumor Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Liver Tumors ◽

Synergistic Effects ◽

Transgenic Zebrafish ◽

Signaling Crosstalk ◽

Specific Expression ◽

Mesenchymal Transition

The poor prognosis for patients with hepatocellular carcinoma (HCC) is related directly to metastasis. The Twist1 gene encodes for a transcription factor essential to embryogenesis. It has also been shown to promote epithelial-to-mesenchymal transition (EMT), invasion, and metastasis; however, there is currently no in vivo evidence that Twist1 plays a role in the metastasis of liver tumors. Zebrafish are increasingly being used as an alternative cancer model. In the current study, an adult-stage zebrafish HCC model was used to examine the synergistic effects of twist1a and xmrk, a well characterized oncogene, during HCC metastasis. We also examined the effects of two inflammatory agents, lipopolysaccharides (LPS) and dextran sulfate sodium (DSS), on the hepatocyte-specific expression of transgenic twist1a and xmrk. The conditional overexpression of twist1a and xmrk was shown to promote liver tumor metastasis in zebrafish, resulting in increased apoptosis and cell proliferation as well as tumor maintenance and propagation independent of the inherent EMT-inducing activity of xmrk. Exposing twist1a+/xmrk+ transgenic zebrafish to LPS or DSS was shown to promote metastasis, indicating that the overexpression of twist1a and xmrk led to crosstalk between the signaling pathways involved in EMT. This study provides important evidence pertaining to the largely overlooked effects of signaling crosstalk between twist1a and xmrk in regulating HCC metastasis. Our results also suggest that the co-expression of twist1a/xmrk in conjunction with exposure to LPS or DSS enhances HCC metastasis, and provides a valuable in vivo platform by which to investigate tumor initiation and metastasis in the study of liver cancer.

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