Liver cancer currently ranks fifth highest of all human cancers in incidence and third highest in cancer mortality. Recent investigations have reported a dramatic increase in the incidence of the liver cancer in the US. The etiology of human liver cancer has been linked to a number of factors including hepatitis B and C infection, mycotoxin exposure, iron overload, and environmental agents. Chronic liver hyperplasia is a common feature in human liver neoplasia development and as such appears to follow the same sequential multi-step process seen in rodent liver. While the hepatocyte is the target of most liver carcinogens, recent evidence suggests that non-parenchymal cells, including the Kupffer cell (the resident liver macrophage), may be an important component of growth regulation in the liver. The Kupffer cell upon activation can produce an array of products, including reactive oxygen intermediates and cytokines, which may impact on cell growth regulation. Little is known about the role of the Kupffer cell in hepatocarcinogenesis. The long term objectives of these studies therefore are to better understand the role that the Kupffer cell plays in this process. The proposed studies will specifically examine whether activation of the Kupffer cell is important in the tumor promotion stage of hepatic tumorigenesis. The overall hypothesis of these studies is that activation of Kupffer cells result in the release of cellular growth regulatory signaling molecules that selectively produce an increase in cell proliferation in initiated cells ultimately leading to hepatic neoplasia. These studies will examine the effect of Kupffer cell activation and deactivation on both normal (noninitiated) and initiated hepatocyte growth, and will determine whether activation hepatic tumor promoting compounds activate Kupffer cells, which result in hepatocyte proliferation. The products of the tumor promoter activated Kupffer cells will be determined and examined for potential hepatocyte growth regulatory effects. In addition, the effect of Kupffer activation, either by LPS (lipopolysaccharide) or hepatic tumors promoters on preneoplastic lesion growth and normal liver growth will be investigated These studies will provide information regarding the interplay between the Kupffer cell and heptatocytes during the tumor promotion stage of hepatocarcinogenesis. These studies will further our understanding into the mechanisms of the development and progression of human liver cancer with potential application to prevention and therapy.
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