Chronic inflammation is a common ground to cancer development - accounting for ~20% of the world-wide cancer load. Hepatocellular carcinoma, the third leading cause of cancer mortality, is a prototype for inflammation-associated cancer, as most of the cases develop on a background of chronic hepatitis. While eliminating the underlying cause (e.g., hepatitis) is many times hard to attain, recent elucidation of inflammation-activated molecular pathways suggests that therapies directed at disrupting these pathways could be useful for cancer prophylaxis in chronic inflammatory states. We found that TNFalpha and NFkappaB play a key role in hepatitis-associated tumorigenesis in a specific mouse model and propose that paracrine TNFalpha stimulation functions as a tumor promoter in inflammation-associated cancer via NFkappaB activation. Short-term anti-TNFalpha treatment induced premalignant hepatocyte apoptosis, and NFkappaB inhibition via a dominant NF-kappaB represser suppressed tumor progression in a mouse model. We will assess the value of anti-TNFalpha prophylaxis in HCC development in a mouse model and determine if it could stabilize the premalignant phase and delay tumor progression. During the course of the proposed study we aim to achieve the following specific goals: 1. Assess the effect of in vivo TNFalpha inhibition on tumor development in Mdr2 knockout mice - a model for hepatitis-associated liver cancer. 2. Study the source of TNFalpha in the Mdr2KO microenvironment in relation to hepatocyte NF-kappaB activation. 3. Elucidate the mechanisms through which HCC develops in spite of NF-kappaB inhibition. Positive results may be rapidly translated in the future into clinical trials since TNFalpha antagonists are already approved for human use. Understanding the mechanisms underlying the response to this treatment and the mechanisms of escape may help to plan effective treatment regimens for clinical studies.
