Stromal Myofibroblasts in Hepatic Carcinogenesis

基质肌成纤维细胞在肝癌发生中的作用

• 批准号: 7244481
• 负责人: DAVID A. BRENNER
• 金额: $ 15.47万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7244481
• 关键词: carcinogenesis; inflammation; liver; retinoids; role

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.

肝硬化是几乎90%的肝细胞癌（HCC）的统一危险因素。慢性 炎症和细胞外基质水平升高是肝硬化的两个关键特征。虽然它有 已经表明，在非实质细胞中促炎途径的慢性激活起主要作用， 在肝癌发生过程中，不知道激活的肌成纤维细胞（MFs）和 肝微结构的后续变化有助于癌的发生。激活的MF不是 仅见于癌前病变或癌旁肝，也可在HCC病灶周围积聚 提示MF与HCC密切相关。我们最近发现激活的肝星状细胞， 肝脏中MFs的主要来源，是受损肝脏中Toll样受体（TLR）4的主要靶点。我们 假设慢性暴露于TLR 4配体有助于促进炎症环境， 癌前病变和MFs，Kupffer形成细胞网络，驱动慢性炎症， 癌前肝细胞和血管生成，并提供了一个小生境，使肝癌的发展。我们将定义 肝癌相关微纤维来源及肝癌相关微纤维间基因表达模式比较 以及小鼠和人类中损伤相关的MF，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竭如何影响化学和生物学特性。 饮食诱导的肝癌发生，使用体内发光，MRI和光学的组合 脱氧血红蛋白显像（Aim 2）。为了确定MF中的促炎信号是否有助于 在肝癌发生过程中，我们将使用双转基因报告基因来监测肝MFs中NF-κ B的活化。 小鼠，并评估正常和骨髓嵌合TLR 4突变小鼠中的肝癌发生， 通过MRI成像检测具有MF特异性IkappaB激酶β缺失的小鼠（目的3）。我们将调查是否 静止的肝星状细胞是维甲酸在体内的主要储存场所，抑制肝癌的发生 通过研究卵磷脂：视黄醇酰基转移酶缺乏的肝癌发生， 小鼠的肝星状细胞中完全不存在类维生素A（Aim 4）。对这四个人的追捕 目的是明确静止和活化的肝成纤维细胞群在肝癌发生中的作用。 并可能指向预防或治疗HCC的新策略。