Stromal Myofibroblasts in Hepatic Carcinogenesis

肝硬变是几乎90%的肝细胞癌的统一危险因素。慢性 炎症和六细胞基质水平升高是肝硬变的两个主要特征。虽然它已经 研究表明，非实质细胞中促炎通路的慢性激活起主要作用。 在肝细胞癌的发生过程中，激活的肌成纤维细胞(MFS)和 随后肝脏微结构的改变有助于癌症的发生。激活的MFS不是 仅见于整个癌前病变或癌变的肝硬变，也可聚集在肝细胞癌病变周围 提示MFS与肝细胞癌之间存在密切的相互作用。我们最近发现，激活的肝星状细胞， MFS在肝脏中的主要来源，是损伤肝脏中Toll样受体(TLR)4的主要靶点。我们 假设慢性暴露于TLR4配体对大鼠前炎症环境有贡献 癌前病变和MFS、Kupffer形成一个细胞网络，驱动慢性炎症、增殖 癌前肝细胞和血管生成，并提供了一个利基，使肝癌的发展。我们将定义 肝癌相关MFS的起源及其相关基因表达模式的比较 以及与损伤相关的MFS，以确定它们是否构成相同的细胞 人口(目标1)。我们将分析肝星状细胞的激活或耗尽如何影响化学和 体内发光体、磁共振和光学相结合的饮食诱发肝癌研究 脱氧血红蛋白成像(目标2)。为了确定MFS中的促炎信号是否有助于 肝癌的发生，我们将使用双转基因报告来监测肝脏MFS中的核因子-kappaB的激活 并评估正常小鼠和骨髓嵌合TLR4突变小鼠的肝癌发生。 通过MRI成像检测到Mf特异性缺失IkappaB激酶β的小鼠(目标3)。我们将调查是否 静止的肝星状细胞是体内维甲酸的主要储存部位，可抑制肝癌的发生 通过研究卵磷脂：视黄醇酰基转移酶缺陷导致肝癌的视黄醇依赖方式 肝星状细胞中完全不含维甲酸的小鼠(目标4)。对这四个人的追求 AIMS将确定静止和激活的肝成纤维细胞群体在肝癌发生中的作用 并可能指向预防或治疗肝细胞癌的新策略。

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.