Non-invasive monitoring of hepatocellular carcinoma in transgenic mouse with bioluminescent imaging.
ABSTRACT A small animal imaging system for hepatocellular carcinoma (HCC)-specific reporter gene expression will enable monitoring of carcinogenesis or therapeutic intervention in vivo. Transgenic mouse was developed in which firefly luciferase (fLuc) expression was controlled by the AFP enhancer/promoter. The bioluminescent signals of the transgenic neonates were strong at their liver region and decreased after birth. Bioluminescent imaging (BLI) of a transgenic mouse treated with N-nitrosodiethylamine revealed distinct fLuc activity in the liver and an increased pattern with time. The transgenic mouse model can be used to monitor AFP producing HCC by a chemical carcinogen in a live animal by BLI.
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ABSTRACT: Accumulated understanding of the molecular pathways regulating cancer progression has led to the development of novel targeted therapies. Hepatocellular carcinoma (HCC) remains a highly lethal disease that is resistant to conventional cytotoxic chemotherapy and radiotherapy. Unlike conventional chemotherapy, molecular-targeted agents offer the potential advantages of a relatively high therapeutic window and use in combination with other anticancer strategies without overlapping toxicity. It is hoped that these drugs will become valuable therapeutic tools within the multimodal approach to treating cancer. A recent clinical trial revealed an oral multikinase inhibitor, sorafenib, as the first agent that has demonstrated improved overall survival in patients with advanced HCC. The present review summarizes molecular abnormalities of HCC with a focus on clinical studies, and current status as well as problems of the targeted strategies for HCC.Cancer Science 12/2008; 100(1):1-8. · 3.48 Impact Factor
- Transplantation 05/1963; 1:174-80. · 3.78 Impact Factor
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ABSTRACT: Non-invasive assessment of transgenic animals using bioluminescence imaging offers a rapid means of evaluating disease progression in animal models of disease. One of the challenges in the field is to develop models with robust expression to image repetitively live intact animals through solid tissues. The prostate-specific antigen (PSA) promoter is an attractive model for studying gene regulation due to its hormonal response and tissue-specificity permitting us to measure signaling events that occur within the native tissues. The use of the GAL4-VP16 activator offers a powerful means to augment gene expression levels driven by a weak promoter. We have used a two-step transcriptional amplification (TSTA) system to develop a transgenic mouse model to investigate the tissue-specificity and developmental regulation of firefly luciferase (fl) gene expression in living mice using bioluminescence imaging. We employed an enhanced prostate-specific promoter to drive the yeast transcriptional activator, GAL4-VP16 (effector). The reporter construct carries five Gal4 binding sites upstream of the fl gene. We generated a transgenic mouse model using a single vector carrying the effector and reporter constructs. The transgenic mice show prostate-specific expression as early as three weeks of age. The bioluminescence signal in the prostate is significantly higher than in other organs. We also demonstrate that blocking androgen availability can downregulate the fl expression in the prostate. The transgenic mice display normal physical characteristics and developmental behavior, indicating that the high level of GAL4 driven expression is well tolerated. These findings suggest that the GAL4-VP16 transactivator can be used to amplify reporter gene expression from a relatively weak promoter in a transgenic mouse model. The transgenic TSTA model in conjunction with other transgenic cancer models should also help to detect and track malignancies. The strategies developed will be useful for transgenic research in general by allowing for amplified tissue specific gene expression.Transgenic Research 03/2005; 14(1):47-55. · 2.61 Impact Factor