Volume 126, Issue 5, Pages 1374-1386 (May 2004) Disruption of β-catenin pathway or genomic instability define two distinct categories of liver cancer in transgenic mice  Diego F. Calvisi, Valentina M. Factor, Sara Ladu, Elizabeth A. Conner, Snorri S. Thorgeirsson  Gastroenterology  Volume 126, Issue 5, Pages 1374-1386 (May 2004) DOI: 10.1053/j.gastro.2004.02.014

Figure 1 Incidence and time course of HCC development in c-myc/TGF-α, c-myc/E2F-1, E2F-1, and c-myc transgenic mice. Gastroenterology 2004 126, 1374-1386DOI: (10.1053/j.gastro.2004.02.014)

Figure 2 Polymorphisms detected by RAPD primers in tumors and their respective surrounding tissues from different transgenic mice. Genetic alterations are indicated by arrows. (A ) D1Byu2 primer amplification resulted in loss of 1 band in TGF-α HCC. The c-myc/TGF-α dysplastic lesion showed a reduction of the intensity in 1 band and loss of another fragment (B) or the loss of 4 bands and an increase in intensity in 1 band (C ) with the D2Byu1 or D3Byu2 primers, respectively. (D) The c-myc/TGF-α HCCs showing the appearance of a new band when amplified by the D4Byu3 primer. Gastroenterology 2004 126, 1374-1386DOI: (10.1053/j.gastro.2004.02.014)

Figure 3 Extent of genomic instability and AFP expression in hepatic lesions from different transgenic mouse lines as detected by RAPD analysis and immunohistochemistry, respectively. Each bar represents mean ± SD for each transgenic line. Five to 15 samples per stage per transgenic line were used for RAPD analysis. Gastroenterology 2004 126, 1374-1386DOI: (10.1053/j.gastro.2004.02.014)

Figure 4 Ideograms of chromosomes affected by genomic abnormalities in malignant tumors from c-myc (A ), c-myc/E2F-1 (B), and c-myc/TGF-α (C ) mice. The homologous regions of the human chromosomes are indicated at the right of the figure. Gastroenterology 2004 126, 1374-1386DOI: (10.1053/j.gastro.2004.02.014)

Figure 5 Immunohistochemical analysis of AFP expression in preneoplastic and neoplastic lesions. (A ) Wild-type liver displaying an absence of AFP immunostaining. (B) A c-myc/TGF-α dysplastic liver showing focal positivity for AFP. (C ) A c-myc/TGF-α HCC showing strong AFP immunolabeling. (D) TGF-α HCC showing intense AFP staining. HCC displayed very faint AFP positivity in E2F-1 (E ) and c-myc/E2F-1 (F ) (original magnification 200×). Gastroenterology 2004 126, 1374-1386DOI: (10.1053/j.gastro.2004.02.014)

Figure 6 Immunohistochemistry of β-catenin expression in preneoplastic and neoplastic lesions developed in different transgenic lines. (A ) A c-myc/E2F-1 eosinophilic focus showing cytoplasmic and nuclear translocation of β-catenin. (B) A c-myc/E2F-1 HCC displaying nuclear accumulation of β-catenin throughout the tumor. (C ) TGF-α neoplastic hepatocytes showing nuclear and cytoplasmic positivity for β-catenin. (D) A c-myc solid carcinoma showing nuclear and cytoplasmic immunolabeling. (E ) A c-myc/TGF-α clear-cell adenoma displaying a reduced membranous staining compared with the normal counterpart (upper right). (F ) Normal membranous β-catenin immunolocalization in an E2F-1 well-differentiated trabecular HCC. (G) A c-myc/TGF-α HCC harboring a β-catenin mutation showing an absence of immunoreactivity for SARP2. (H ) A c-myc/TGF-α HCC with loss of β-catenin displaying intense SARP2 immunolabeling (original magnification 200×) Gastroenterology 2004 126, 1374-1386DOI: (10.1053/j.gastro.2004.02.014)

Figure 7 Effect of MeIQx treatment on genomic instability in c-myc transgenic mice. Each bar represents mean ± SD. Five to 15 samples per stage per group were used for RAPD analysis. Gastroenterology 2004 126, 1374-1386DOI: (10.1053/j.gastro.2004.02.014)