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 #
1R01CA127228-01A1
Application #
7372826
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Jhappan, Chamelli
Project Start
2007-09-26
Project End
2012-07-31
Budget Start
2007-09-26
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
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
Lee, Jung Il; Wright, Jocelyn H; Johnson, Melissa M et al. (2016) Role of Smad3 in platelet-derived growth factor-C-induced liver fibrosis. Am J Physiol Cell Physiol 310:C436-45
Riehle, Kimberly J; Hoagland, Vicki; Benz, Whitney et al. (2014) Hepatocellular heme oxygenase-1: a potential mechanism of erythropoietin-mediated protection after liver ischemia-reperfusion injury. Shock 42:424-31
Wright, Jocelyn H; Johnson, Melissa M; Shimizu-Albergine, Masami et al. (2014) Paracrine activation of hepatic stellate cells in platelet-derived growth factor C transgenic mice: evidence for stromal induction of hepatocellular carcinoma. Int J Cancer 134:778-88
Riehle, Kimberly J; Johnson, Melissa M; Johansson, Fredrik et al. (2014) Tissue-type plasminogen activator is not necessary for platelet-derived growth factor-c activation. Biochim Biophys Acta 1842:318-25
Hayes, Brian J; Riehle, Kimberly J; Shimizu-Albergine, Masami et al. (2014) Activation of platelet-derived growth factor receptor alpha contributes to liver fibrosis. PLoS One 9:e92925
Riehle, Kimberly J; Haque, Jamil; McMahan, Ryan S et al. (2013) Sustained Glutathione Deficiency Interferes with the Liver Response to TNF-? and Liver Regeneration after Partial Hepatectomy in Mice. J Liver Disease Transplant 1:
McMahan, Ryan S; Riehle, Kimberly J; Fausto, Nelson et al. (2013) A disintegrin and metalloproteinase 17 regulates TNF and TNFR1 levels in inflammation and liver regeneration in mice. Am J Physiol Gastrointest Liver Physiol 305:G25-34
Fernando, Joan; Sancho, Patricia; Fernandez-Rodriguez, Conrado M et al. (2012) Sorafenib sensitizes hepatocellular carcinoma cells to physiological apoptotic stimuli. J Cell Physiol 227:1319-25
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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