Intrahepatic cholangiocarcinomas are highly malignant adenocarcinomas with high morbidity and mortality rates, and limited treatment options. During the previous grant period, we obtained preliminary data supporting the establishment of a unique preclinical rat model of rapid intrahepatic cholangiocarcinoma growth and progression that recapitulates clinical as well as key cellular and molecular features of the human disease. Most notably, we identified with this model, based on orthotopic cell transplantation of mutationally-activated ErbB-2/Neu transformed rat cholangiocytes into the livers of isogenic rats, a positive correlation between bile duct obstruction and enhanced tumor growth, suggesting a new and important growth regulatory mechanism that may have great significance as a novel promoting stimulus relevant to human cholangiocarcinoma growth and progression. Our previous work also demonstrated a link between ErbB-2/Neu overexpression and cyclooxygenase-2 up-regulation in cholangiocarcinoma, supporting an important role for these molecular pathways in cholangiocarcinogenesis. Even more recently, we achieved for the first time spontaneous neoplastic transplantation of rat cholangiocytes, which was found to be associated with a significant up-regulation of cyclooxygenase-2 together with prominent activation of Akt, but surprisingly not with enhanced ErbB-2/Neu expression or signaling. Interestingly, these spontaneously transformed cholangiocytes were only intermediately tumorigenic when compared with ErbB-2/Neu transformants that also overexpressed cyclooxygenase-2. We now propose to extend our preliminary findings by (1) exploring mechanisms and regulators of altered cholangiocarcinoma growth following bile duct obstruction, as well as employing state-of-the art molecular and quantitative immunohistochemical technologies of gene expression profiling to provide a comprehensive picture of the differences among our unique neoplastic rat cholangiocyte cell lines and their growth responses in vitro and in vivo, and (2) elucidate the functional regulatory relationships between cyclooxygenase-2 up-regulation and Akt activation in in vitro spontaneous transformation of rat cholangiocytes, and the role played by HGF and TGF-? in promoting the malignant potential of these cells. The proposed research is highly significant since it will establish a powerful new model of cholangiocarcinoma that can be of great value for preclinical testing of target based therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039225-25
Application #
7812168
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Blair, Donald G
Project Start
1996-02-16
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
25
Fiscal Year
2010
Total Cost
$288,953
Indirect Cost
Name
Virginia Commonwealth University
Department
Pathology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Sirica, Alphonse E; Gores, Gregory J (2014) Desmoplastic stroma and cholangiocarcinoma: clinical implications and therapeutic targeting. Hepatology 59:2397-402
Liu, Runping; Zhao, Renping; Zhou, Xiqiao et al. (2014) Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2. Hepatology 60:908-18
Fingas, Christian D; Mertens, Joachim C; Razumilava, Nataliya et al. (2013) Polo-like kinase 2 is a mediator of hedgehog survival signaling in cholangiocarcinoma. Hepatology 58:1362-74
Mertens, Joachim C; Fingas, Christian D; Christensen, John D et al. (2013) Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res 73:897-907
Campbell, Deanna J W; Dumur, Catherine I; Lamour, Nadia F et al. (2012) Novel organotypic culture model of cholangiocarcinoma progression. Hepatol Res 42:1119-30
Fingas, Christian D; Mertens, Joachim C; Razumilava, Nataliya et al. (2012) Targeting PDGFR-? in Cholangiocarcinoma. Liver Int 32:400-9
Sirica, Alphonse E (2012) The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 9:44-54
Sirica, Alphonse E; Campbell, Deanna J; Dumur, Catherine I (2011) Cancer-associated fibroblasts in intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol 27:276-84
Fingas, Christian D; Bronk, Steven F; Werneburg, Nathan W et al. (2011) Myofibroblast-derived PDGF-BB promotes Hedgehog survival signaling in cholangiocarcinoma cells. Hepatology 54:2076-88
Fingas, Christian D; Blechacz, Boris R A; Smoot, Rory L et al. (2010) A smac mimetic reduces TNF related apoptosis inducing ligand (TRAIL)-induced invasion and metastasis of cholangiocarcinoma cells. Hepatology 52:550-61

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