Page 60 - ebook HCC

58 PROGRAMME AND ABSTRACTS GENEVA, SWITZERLAND EASL HCC SUMMIT 59
FEBRUARY 13 - 16, 2014

MODELS AND PATHWAYS OF HEPATITIS C VIRUS LIVER INFLAMMATION, OBESITY AND CANCER
ASSOCIATED LIVER CANCER
Michael Karin , Hayato Nakagama , Atusushi Yumemura , Debanjan Dhar ,
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Joan Font Burjada , Eek Jun Park 1
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Thomas Pietschman 1 1 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology
1 Division Experimental Virology, TWINCORE - Centre for Experimental and Clinical and Pathology, UCSD School of Medicine, San Diego, United States
Infection Research, Hannover, Germany
Corresponding author’s e-mail: karinoffice@ucsd.edu
Corresponding author’s e-mail: thomas.pietschmann@twincore.de
Obesity increases cancer risk and its effect is most notable on liver cancer, whose risk
Chronic hepatitis C virus infection (HCV) is associated with liver disease including is 4.5-fold higher in men with BMI > 35. In fact, obesity is one of the major drivers of
development of hepatocellular carcinoma (HCC). In fact, HCV infection is one of the prime hepatocellucar carcinoma (HCC) in the US. We have shown that feeding with high fat
reasons for development of liver cancer and in turn a key indication for liver transplantation. diet (HFD) or genetic obesity strongly potentiate the induction of HCC in male mice given
Despite of intensive research, the pathways leading to HCV-driven hepatocellular
BASIC SPEAKERS ABSTRACTS model systems to dissect molecular pathways of HCV-associated liver cancer. While the STAT3 activation. In addition, consumption of HFD results in activation of mTORC1 and BASIC SPEAKERS ABSTRACTS
the chemical pro-carcinogen diethyl nitrosamine (DEN). Part of this increase is due to
carcinoma are still incompletely understood. This is certainly in part due to lack of robust
TNF driven inflammatory signaling in hepatocytes that leads to upregulation of IL-6 and
Chimpanzee model in many ways recapitulates key features of HCV infection in humans,
phosphorylation of its downstream targets. We used rapamycin to interrogate the role of
mTORC1 and found that although it inhibited hepatic steatosis it led to enhanced IL-6
these animals do not develop HCC. Moreover, ethical concerns clearly limit utility of this
model. Nevertheless, important in vitro and in vivo model systems have been developed
production and STAT3 activation. Although this effect may be due to mTORC1 inhibition
and contributed important pieces to our current understanding of HCV-induced HCC.
in macrophages, we found that hepatocyte specific deletion of Raptor (an essential
These models include transgenic mice ectopically expressing various viral proteins and
obese animals. To further understand the mechanism of hepatocarcinogenesis and how
cultured cells transfected or infected with replicons or fully infectious HCV. Accumulated
evidence derived from these models indicates that HCV elicits indirect effects including an scaffold of mTORC1) strongly potentiated the induction of HCC by DEN in both lean and
it is affected by HFD we developed new procedures for isolation of HCC projection cells
inflammatory and profibrotic host response thus contributing to carcinogenesis. However, (HcPC ) from pre-malignant lesions. These cells can give rise to HCC after transplantation
in addition mounting data support the notion that HCV also exerts direct effects on infected into MUP-uPA transgenic mice, whose livers suffer transient liver damage due to ER
cells that may promote their malignant transformation. In that regard viral factors have been stress. The progression of HcPC to HCC depends on autocrine production of IL-6 and is
reported to modulate cellular signaling cascades crucial for regulation of cell proliferation strongly stimulated by feeding the MUP-uPA recipients with HFD. Interestingly, MUP-uPA
and survival including the p53 and retinoblastoma pathways. Moreover, some host factors mice given HFD develop classical non-alcoholic steatohepatitis (NASH) accompanied by
utilized by HCV have been implicated as tumor suppressors including miRNA-122 and massive leukocyte and lymphocyte infiltration into the liver. In this model, obesity-promoted
Claudins. Therefore, dysregulation of the function of these cellular factors may in addition HcPC to HCC progression and NASH development are highly dependent on TNF receptor
contribute to development of liver cancer. Future research into these pathways may 1 (TNFR1) signaling activated by TNF produced by infiltrating macrophages that are
ultimately reveal new targets for intervention with HCV-dependent liver disease. activated by DAMPs that are released by hepatocytes that undergo lipotoxic stress due to
fatty acid exposure and ER stress. Anti-TNF drugs can attenuate tumor progression and
clinical evidence suggests that TNF also has a role in the pathogenesis of human NASH
and its progression to HCC.