Hepatic cirrhosis is the unifying risk factor for almost 90% of hepatocellular carcinomas (HCC). Chronic inflammation and increased levelsextracellular matrix are two key features of hepatic cirrhosis. While it has been shown that chronic activation of proinflammatory pathways in non-parenchymal cells plays a major role in hepatocarcinogenesis, it is not known whether accumulation of activated myofibroblasts (MFs) and subsequent changes in the hepatic microarchitecture contribute to carcinogenesis. Activated MFs are not only found throughout the premalignant or malignant cirrhotic liver, but also accumulate around HCC lesion suggesting 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. We hypothesize that chronic exposure to TLR 4 ligands contributes to the profinflammatory environment of the preneoplastic and that MFs, Kupffer form a cellular network that drives chronic inflammation, proliferation of premalignant hepatocytes and angiogenesis and provides a niche that allow HCC to develop. We will define the origin of HCC-associated MFs and compare gene expression patterns between HCC-associated MFs and injury-associated MFs in mice and humans to determine whether they constitute the same cell population (Aim 1). We will analyze how activation or depletion of hepatic stellate cells affects chemical- and diet-induced hepatocarcinogenesis using a combination of in vivo luminescene, MRI and optical deoxyhemoglobin imaging (Aim 2). To determine whether proinflammatory signaling in MFs contributes to hepatocarcinogenesis, we will monitor NF-kappaB activation in hepatic MFs using a double transgenic reporter mouse, and assess hepatocarcinogenesis in normal and bone-marrow chimeric TLR4-mutated mice and mice with a MF-specific deletion of IkappaB kinase beta by MRI imaging (Aim 3). We will investigate whether quiescent hepatic stellate cell, the major storage site of retinoids in the body, suppress hepatocarcinogenesis in a retinoid-dependent manner by studying hepatocarcinogenesis in lecithin:retinol acyltransferase-deficient mice which display a complete absence of retinoids in hepatic stellate cells (Aim 4). The pursuit of these four aims will define the role of quiescent and activated hepatic fibroblast populations in hepatocarcinogenesis and may point towards novel strategies for the prevention or treatment of HCC.
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