The most recent result in this project include.(1)A comprehensive understanding of molecular mechanisms driving cancer onset and progression should provide a basis for improving early diagnosis, biomarker discovery and treatment options. A key value of genetically engineered mice for modeling human cancer is the possibility to analyze the entire process of tumor development. Here, we applied functional genomics approach to study step-bystep development of hepatocellular carcinoma (HCC) in the c-Myc/ Tgfa transgenic mouse model of aggressive human liver cancer.We report that coexpression of c-Myc and Tgfa induces progressive and cumulative transcriptional alterations in the course of liver oncogenesis. Functional analysis of deregulated genes at the early stage of HCC disease supports a model of active hepatocyte proliferation on the background of chronic oxidative stress generated by a general metabolic disorder. In addition, early and persistent deregulation of numerous immune-related genes suggested that disruption of immune microenvironment may contribute to oncogenic process in this model of accelerated liver carcinogenesis. In particularly, by flow cytometry analysis, we found loss of the major histocompatibility complex class I expression in dysplastic hepatocytes followed by upregulation of numerous activating ligands for natural killer (NK) cells concomitant with a drastic decrease in hepatic NK cell frequency. In conclusion, our study provides a comprehensive characterization of sequential molecular changes during a stepwise progression of preneoplastic lesions toward HCC and highlights a critical role of metabolic disorders and innate immunity at the early stages of liver cancer.(2)Hepatocellular carcinoma (HCC) is the third cancer killer worldwide with >600,000 deaths every year. Although the major risk factors are known, therapeutic options in patients remain limited in part because of our incomplete understanding of the cellular and molecular mechanisms influencing HCC development. Evidence indicates that the retinoblastoma (RB) pathway is functionally inactivated in most cases of HCC by genetic, epigenetic, and/or viral mechanisms. To investigate the functional relevance of this observation, we inactivated the RB pathway in the liver of adult mice by deleting the three members of the Rb (Rb1) gene family: Rb, p107, and p130. Rb family triple knockout mice develop liver tumors with histopathological features and gene expression profiles similar to human HCC. In this mouse model, cancer initiation is associated with the specific expansion of populations of liver stem/progenitor cells, indicating that the RB pathway may prevent HCC development by maintaining the quiescence of adult liver progenitor cells. In addition, we show that during tumor progression, activation of the Notch pathway via E2F transcription factors serves as a negative feedback mechanism to slow HCC growth. The level of Notch activity is also able to predict survival of HCC patients, suggesting novel means to diagnose and treat HCC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011170-03
Application #
8349367
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2011
Total Cost
$364,963
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Coulouarn, C├ędric; Corlu, Anne; Glaise, Denise et al. (2012) Hepatocyte-stellate cell cross-talk in the liver engenders a permissive inflammatory microenvironment that drives progression in hepatocellular carcinoma. Cancer Res 72:2533-42
Thomas, Hala Elnakat; Mercer, Carol A; Carnevalli, Larissa S et al. (2012) mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma. Sci Transl Med 4:139ra84
Coulouarn, Cedric; Factor, Valentina M; Conner, Elizabeth A et al. (2011) Genomic modeling of tumor onset and progression in a mouse model of aggressive human liver cancer. Carcinogenesis 32:1434-40
Andersen, Jesper B; Loi, Roberto; Perra, Andrea et al. (2010) Progenitor-derived hepatocellular carcinoma model in the rat. Hepatology 51:1401-9
Coulouarn, C; Factor, V M; Andersen, J B et al. (2009) Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene 28:3526-36
Zimonjic, Drazen B; Ullmannova-Benson, Veronika; Factor, Valentina M et al. (2009) Recurrent and nonrandom DNA copy number and chromosome alterations in Myc transgenic mouse model for hepatocellular carcinogenesis: implications for human disease. Cancer Genet Cytogenet 191:17-26
Coulouarn, Cedric; Factor, Valentina M; Thorgeirsson, Snorri S (2008) Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology 47:2059-67
Ladu, Sara; Calvisi, Diego F; Conner, Elizabeth A et al. (2008) E2F1 inhibits c-Myc-driven apoptosis via PIK3CA/Akt/mTOR and COX-2 in a mouse model of human liver cancer. Gastroenterology 135:1322-32