Stromal Myofibroblasts in Hepatic Carcinogenesis

Columbia University Health Sciences, New York NY

Investigators

Linked publications & trials

Abstract

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