Article first published online: 14 DEC 2007
Copyright © 2007 American Association for the Study of Liver Diseases
Volume 47, Issue 4, pages 1178–1190, April 2008
How to Cite
Sirica, A. E., Zhang, Z., Lai, G.-H., Asano, T., Shen, X.-N., Ward, D. J., Mahatme, A. and DeWitt, J. L. (2008), A novel “patient-like” model of cholangiocarcinoma progression based on bile duct inoculation of tumorigenic rat cholangiocyte cell lines. Hepatology, 47: 1178–1190. doi: 10.1002/hep.22088
Presented in part at the 2006 annual meeting of the American Association for the Study of Liver Diseases in Boston, MA, (Hepatology 2006;44(Suppl):526A), at Experimental Biology 2007 in Washington, DC, (FASEB J 2007;21:A71), and at Digestive Disease Week 2007 in Washington, DC. (Gastroenterology 2007;132(Suppl):A-730).
Potential conflict of interest: Nothing to report.
- Issue published online: 25 MAR 2008
- Article first published online: 14 DEC 2007
- Manuscript Accepted: 11 OCT 2007
- Manuscript Received: 17 MAY 2007
- National Institutes of Health. Grant Numbers: R01 CA 83650, R01 CA 39225
Intrahepatic cholangiocarcinoma typically presents in an advanced stage in which treatment options are limited. In an effort to recapitulate key biological and clinical features of the progressive disease, we established a novel rat model based on bile duct inoculation of rat cholangiocyte cell lines in different stages of tumor progression. Our BDEneu cell line, which is highly tumorigenic, originated from an immortalized rat cholangiocyte cell line (BDE1 cells) that was stably transfected to constitutively overexpress mutationally activated rat neu oncogene. Our less aggressive tumorigenic BDEsp cholangiocyte cell line was derived from the spontaneous in vitro neoplastic transformation of the same parent BDE1 cell line. Unlike BDEneu cells, BDEsp cells expressed wild-type c-neu and exhibited in vitro growth rates intermediate between those of BDEneu and BDE1 cholangiocytes. Cyclooxygenase-2 and activated Akt were significantly overexpressed in BDEsp cells over those of BDE1 cells, and at higher levels than those expressed in BDEneu cells. Only BDEneu cells overexpressed activated p185neu, which was associated with a significant increase in phospho-p44/42 mitogen-activated protein kinase (MAPK). Mucin 1 (MUC1) messenger RNA (mRNA), an indicator of cholangiocarcinoma cell progression, was also significantly overexpressed in BDEneu cells over that of BDEsp cells. BDEneu cells inoculated into the bile duct of isogenic rats resulted over a 21- to 26-day period in rapid exponential cholangiocarcinoma tumor growth within liver, paralleled by increases in bile duct obstruction and gross peritoneal metastases. Under comparable conditions, BDEsp cells yielded only small nonmetastatic intrahepatic cholangiocarcinomas without bile duct obstruction. Conclusions: A novel model of cholangiocarcinoma progression mimicking progressive development of the advanced human disease has been established, which may serve as a powerful preclinical platform to study cholangiocarcinoma progression and for rapidly testing treatment approaches. (HEPATOLOGY 2008.)