Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Although the risk factors for HCC are well known, its prognosis is poor due, in part, to lack of precise knowledge about the molecular pathogenesis of this cancer. Effective therapeutic strategies for HCC include the prevention or regression of cirrhosis, and the prevention of tumor development in the cirrhotic liver. HCC is a very genetically heterogeneous tumor with a high frequency of multiple genomic alterations. Yet, it is not known whether the frequency of DNA mutations is increased in fibrotic or cirrhotic livers, or whether the prevention or regression of fibrosis would prevent HCC development. One of the difficulties in conducting experimental studies on the pathogenesis of HCC is the lack of good animal models that incorporate fibrosis and/or cirrhosis in the progression to cancer. We have developed a novel model of liver fibrosis that involves the hepatic over-expression of platelet-derived growth factor C (PDGF-C) in mice. These mice develop liver fibrosis in a pattern that resembles that of patients with non-alcoholic fatty liver disease or chronic alcoholism. Fibrosis is preceded by activation and proliferation of hepatic stellate cells, and is followed by angiogenesis, the development of dysplastic lesions, and progression to HCCs by 8 months of age. Based on our animal studies and our findings of abnormal expression of PDGF-C in human liver disease, we hypothesize that PDGF-C is a key molecule in the pathogenesis of liver fibrosis and HCC. In this application we propose to use this unique transgenic mouse model to a) determine whether TGF?/Smad cellular pathways are essential to fibrogenesis and carcinogenesis by using genetically modified mice and b) whether i) small molecule inhibitors and ii) sh-RNA viral expression block disease progression. Using a novel sensitive PCR assay to detect random mutations, c) we will also determine a) whether the frequency of DNA mutations increases as liver disease progresses from fibrosis to HCC in our rodent model, and b) whether human HCCs have an elevated frequency of random nuclear mutations compared to surrounding non- tumor tissue and non-diseased liver.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA127228-04
Application #
7884607
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Jhappan, Chamelli
Project Start
2006-09-12
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$296,400
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Okada, Hikari; Honda, Masao; Campbell, Jean S et al. (2012) Acyclic retinoid targets platelet-derived growth factor signaling in the prevention of hepatic fibrosis and hepatocellular carcinoma development. Cancer Res 72:4459-71
Lai, Keane K Y; Shang, Sufen; Lohia, Neha et al. (2011) Extracellular matrix dynamics in hepatocarcinogenesis: a comparative proteomics study of PDGFC transgenic and Pten null mouse models. PLoS Genet 7:e1002147

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