To investigate the role that ErbB 2 activation plays in the development of gallbladder carcinoma (GBC), we assessed the levels of ErbB 2 in gallbladder carcinomas developed from BK 5. ErbB 2transgenic mice (ErbB 2 mice) (Kiguchi, K. et al. Cancer Res.,61: 6971,2001). Gallbladders from 52 BK 5. ErbB 2 transgenic mice aged 3 months were analyzed for ErbB 2 and p-ErbB 2 levels. Histological analysis of the gallbladders from transgenic mice revealed the following: 4 were diagnosed as normal (8%),14 had hyperplasia of the epithelial lumen (27%), and 34 were diagnosed as adenocarcinoma (65%). Analysis of the transgenic mice diagnosed as adenocarcinoma of the gallbladder revealed that GBC evolved by two distinct etiological pathways, carcinoma arising from hyperplasia in focal lesion (Type HIF Ca,41%) or hyperplasia in whole epithelium (Type HIW Ca,59%). Type HIW Ca had a higher frequency of invasiveness (70%, p<0.01) compared with that of Type HIF Ca (14%). Immunohistochemical analysis revealed that in the gallbladders of ErbB 2 mice, p-ErbB 2 (phosphorylated ErbB 2 active form of ErbB 2) was detected in areas of hyperplasia of the gallbladder and in both Type HIF and HIW Ca gallbladders. Strong expression of p-ErbB 2 was also observed in areas of invasion. These results not only suggest that GBC may arise via two distinct pathways in the ErbB 2 mice, but these pathways are reminiscent of the adenoma-carcinoma sequence and dysplasia-carcinoma sequence observed in human GBC. In addition, in this mouse model our analyses of ErbB 2 expression and activation in normal, precancerous, and neoplastic lesions revealed that active levels of ErbB 2 (p-ErbB 2) correlate with tumor progression.
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