Hepatic cirrhosis is the unifying risk factor for almost 90% of hepatocellular carcinomas (HCC). Chronicinflammation and increased levelsextracellular matrix are two key features of hepatic cirrhosis. While it hasbeen shown that chronic activation of proinflammatory pathways in non-parenchymal cells plays a major rolein hepatocarcinogenesis, it is not known whether accumulation of activated myofibroblasts (MFs) andsubsequent changes in the hepatic microarchitecture contribute to carcinogenesis. Activated MFs are notonly found throughout the premalignant or malignant cirrhotic liver, but also accumulate around HCC lesionsuggesting that MFs and HCC interact closely. We have recently shown that activated hepatic stellate cells,the main source of MFs in the liver, are a main target of Toll-like receptor (TLR) 4 in the injured liver. Wehypothesize that chronic exposure to TLR 4 ligands contributes to the profinflammatory environment of thepreneoplastic and that MFs, Kupffer form a cellular network that drives chronic inflammation, proliferation ofpremalignant hepatocytes and angiogenesis and provides a niche that allow HCC to develop. We will definethe origin of HCC-associated MFs and compare gene expression patterns between HCC-associated MFsand injury-associated MFs in mice and humans to determine whether they constitute the same cellpopulation (Aim 1). We will analyze how activation or depletion of hepatic stellate cells affects chemical- anddiet-induced hepatocarcinogenesis using a combination of in vivo luminescene, MRI and opticaldeoxyhemoglobin imaging (Aim 2). To determine whether proinflammatory signaling in MFs contributes tohepatocarcinogenesis, we will monitor NF-kappaB activation in hepatic MFs using a double transgenic reportermouse, and assess hepatocarcinogenesis in normal and bone-marrow chimeric TLR4-mutated mice andmice with a MF-specific deletion of IkappaB kinase beta by MRI imaging (Aim 3). We will investigate whetherquiescent hepatic stellate cell, the major storage site of retinoids in the body, suppress hepatocarcinogenesisin a retinoid-dependent manner by studying hepatocarcinogenesis in lecithin:retinol acyltransferase-deficientmice which display a complete absence of retinoids in hepatic stellate cells (Aim 4). The pursuit of these fouraims will define the role of quiescent and activated hepatic fibroblast populations in hepatocarcinogenesisand may point towards novel strategies for the prevention or treatment of HCC.
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