Application of comparative functional genomics to select mouse models to study human liver cancer: Genetically modified mice have been used extensively for analyzing the molecular events that occur during tumor development. However, in many instances, if not all, it is uncertain to what extent mouse models reproduce features observed in the corresponding human conditions. This uncertainty results largely from the lack of precise methods with which to directly and comprehensively compare mouse and human tumors at the molecular level. We have used global gene expression patterns of 68 hepatocellular carcinomas (HCC) from seven different mouse models and 91 human HCC from predefined subclasses to compare molecular features of mouse and human HCC directly. Gene expression patterns in HCCs from Myc, E2f1 and Myc/E2f1 transgenic mice are most similar to those of the better survival group (subclass B) of human HCC, whereas the expression patterns in HCC from Myc/TGF-a transgenic mice and in diethylnitrosamine-induced mouse HCC are most similar to those of the poorer survival group (subclass A) of human HCC. Gene expression patterns in HCC from Acox1-/- mice and from mice exposed to ciprofibrate are least similar to those observed in human HCC. We conclude that this approach, comparative functional genomics, can effectively identify mouse models that are most appropriate for the analysis of the molecular pathogenesis of human liver cancers. Comparative functional genomics may provide a general method for selecting the most relevant mouse models for other human cancers. Two distinct categories of liver cancer in transgenic mouse models are characterized by disruption of a-catenin pathway and genomic instability: Human liver cancer can be separated into two broad categories that are characterized by activation of a-catenin and genomic instability, respectively. We investigated the role of a-catenin activation and genomic instability in the sequential steps of mouse hepatocarcinogenesis. A large collection of preneoplastic and neoplastic liver lesions from c myc, TGFa, E2F1, c-myc/TGFa and c-myc/E2F1 transgenic mice were analyzed for mutations and deletions in the a-catenin gene by PCR and sequence screening. Activation of a-catenin was investigated by immunohistochemistry (IHC). The RAPD method was used to assess the overall genomic instability in the same lesions. Chromosomal loci affected by genomic alterations were determined by microsatellite analysis. As a prognostic marker, expression of alpha-fetoprotein (AFP) was determined by IHC. Based on these characteristics, liver tumors from the transgenic mouse lines comprise two categories. The first category, exemplified by HCCs from c myc/E2F1 transgenic mice, is characterized by a high frequency of a-catenin activation in the presence of a relatively stable genome and low AFP levels. The second category, represented by c-myc/TGFa HCCs, has a low rate of a-catenin activation, but extensive genomic instability, with recurrent losses of heterozygosity of chromosomes 1, 2, 4, 6, 7, 9, 12, 14, X. In this group, genomic instability is evident from an early dysplastic stage and occurs concomitantly with elevated expression of AFP. Our data indicate that a-catenin activation and genomic instability define two major genetic events during development of mouse liver tumors, similar to those described for human HCCs, providing additional support for our opinion that these transgenic mice are suitable genetic models with which to elucidate the molecular features of human HCC. Vitamin E down-modulates iNOS and NADPH oxidase in c-Myc/TGF-a transgenic mouse model of liver cancer: Co-expression of c-Myc and TGFa in the mouse liver accelerates hepatocarcinogenesis and enhances DNA damage due to chronic oxidative stress.
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