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SUMMARY:Inflammation\, metabolism\, ageing and cancer: Dangerous Liaisons 
 - Michael Karin\, University of California\, San Diego
DTSTART:20101111T130000Z
DTEND:20101111T140000Z
UID:TALK27042@talks.cam.ac.uk
CONTACT:Kate Davenport
DESCRIPTION:Chronic inflammation\, obesity and old age greatly increase ca
 ncer risk. To understand the association and interplay between these risk 
 factors\, we have focused on cancer of the liver\, one of the most metabol
 ically active tissues\, which also has important immune functions. The mos
 t common form of liver cancer\, hepatocellular carcinoma (HCC)\, usually a
 rises in the context of chronic liver disease\, such as cirrhosis\, viral 
 hepatitis and non alcoholic fatty liver disease (NAFLD). Using chemically 
 induced HCC in mice as an experimental model\, we found that inactivation 
 of NF-kappaB or p38alpha signaling in hepatocytes results in enhanced accu
 mulation of reactive oxygen species (ROS) and augmented hepatocyte death\,
  changes that accelerate HCC development. ROS accumulation and oxidative s
 tress lead to activation of Jun kinases (JNK) and JAK2\, resulting in elev
 ated AP-1 and STAT3 activities. Accordingly\, total JNK1 ablation and hepa
 tocyte-specific deletions of c-Jun or STAT3 inhibit the development of che
 mically-induced HCC. We also investigated how obesity enhances HCC develop
 ment using a model of obesity-promoted chemically-induced HCC. Our results
  indicate that obesity leads to hepatosteatosis which results in metabolic
  alterations and chronic inflammation. Inhibition of steatohepatitis throu
 gh ablation of either type 1 TNF receptor (TNFR1) or interleukin 6 (IL-6) 
 abolishes the tumor promoting effect of obesity. Another important factor 
 in obesity-promoted HCC is TORC1\, whose activation results in inhibition 
 of autophagy and its sequella. \nAlthough HCC is one of the most lethal ca
 ncers with a 5-year survival rate of 5%\, it is very slow growing. Thus\, 
 early detection of HCC may provide an opportunity for therapeutic interven
 tion before the cancer becomes too aggressive and refractory to therapy. T
 o this end\, we have isolated from livers of mice treated with the chemica
 l carcinogen diethylnitrosamine (DEN) a population of pre-malignant cells 
 that can give rise to HCC when transplanted into a suitable host. These ce
 lls\, which we named HCC initiating cells (HIC)\, are not as transformed a
 s HCC cells and display unique properties that should enable both their ea
 rly detection as well as elimination. \n
LOCATION:Cancer Research UK Cambridge Research Institute\, Lecture Theatre
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