Promotion of Hepatocellular Carcinoma by Myofibroblasts

事实是：(I)80%的肝细胞癌(HC)发生在纤维化的肝脏中，(Ii)慢性损伤， 炎症和纤维化足以诱发肝细胞癌表明，肝细胞癌真正代表了 在这里，我们试图研究肌成纤维细胞激活是如何促进肝癌的，最终目标是 定义肝脏肿瘤微环境(TME)中的“可用药”靶点。在前两个目标中，我们将重点关注 在肌成纤维细胞中激活肿瘤促进表型的上游通路。我们之前已经 证实了肠道微生物区系和TLR4在肝脏肌成纤维细胞激活中的关键作用。我们的 初步数据显示，肠道微生物区系和TLR4促进了肝癌的发生。我们假设肿瘤促进了 肠道微生物区系和TLR4的作用是由肌成纤维细胞介导的，并将对此进行测试 研究肌成纤维细胞特异性小鼠的肝癌发生和肌成纤维细胞激活的假说 TLR4缺失和在无菌小鼠中(目标1)。我们假设慢性上皮损伤促进 肝细胞癌通过损伤相关分子模式(DAMP)的释放和DAMP介导 肌成纤维细胞激活。我们将检验这样的假设，即阻尼剂ATP和HMGB1促进 ATP受体P2X7或肝细胞特异性基因缺失小鼠的肌成纤维细胞活化与肝细胞癌 HMGB1缺失(目标2)。在最后两个目标中，我们将重点介绍肌成纤维细胞所通过的效应通路 促进肝细胞癌的发展。为了确定肌成纤维细胞是否通过细胞外基质(ECM)促进肝癌，我们 将使用lhx缺失的模型来研究自发性肝纤维化是否增加了肝细胞癌 增加ECM合成和交联度(目标3)。为了确定肌成纤维细胞中的炎症信号 为了促进肝细胞癌，我们将评估IKK基因缺失或激活的小鼠的肝癌发生。 肌成纤维细胞和缺乏表观调节素的小鼠，一种受NF-KB调控的高表达的肝分裂原 肝肌成纤维细胞(目标4)。对人肌成纤维细胞和人肝癌的详细研究将证实 所有上述途径的临床相关性。我们预计拟议的研究将揭示 TME中的可药物靶点，从而导致治疗或预防肝细胞癌的新概念。

The fact that (i) 80% of hepatocellular carcinomas (HCCs) arise in fibrotic livers and that (ii) chronic injury, inflammation and fibrosis are sufficient to induce HCC suggest that HCC truly represents "a wound that does not heal". Here we seek to investigate how myofibroblast activation promotes HCC with the ultimate goal to define "druggable" targets in the hepatic tumor microenvironment (TME). In the first two Aims we will focus on upstream pathways that activate a tumor-promoting phenotype in myofibroblasts. We have previously demonstrated a crucial role for the gut microbiota and TLR4 in hepatic myofibroblast activation. Our preliminary data show promotion of HCC by the gut microbiota and TLR4. We hypothesize that the tumorpromoting effects of the gut microbiota and TLR4 are mediated by myofibroblasts and will test this hypothesis by investigating hepatocarcinogenesis and myofibroblast activation in mice with myofibroblastspecific TLR4 deletion and in germ-free mice (Aim 1). We hypothesize that chronic epithelial injury promotes HCC through the release of damage-associated molecular patterns (DAMPs) and DAMP-mediated myofibroblast activation. We will test the hypothesis that the DAMPs ATP and HMGB1 promote myofibroblast activation and HCC in mice with deletion of the ATP receptor P2X7 or a hepatocyte-specific HMGB1 deletion (Aim 2). In last two Aims, we will focus on effector pathways through which myofibroblasts promote HCC. To determine whether myofibroblasts promote HCC through extracellular matrix (ECM), we will investigate whether spontaneous liver fibrosis increases HCC using a model in which Lhx deletion increases ECM synthesis and cross-linking (Aim 3). To determine whether inflammatory signals in myofibroblasts promote HCC, we will assess hepatocarcinogenesis in mice with deletion or activation of IKK(3 in myofibroblasts and in mice that lack epiregulin, an NF-KB-regulated hepatomitogen with high expression in hepatic myofibroblasts (Aim 4). Detailed studies in human myofibroblasts and human HCC will confirm the clinical relevance of all above described pathways. We anticipate that the proposed studies will reveal druggable targets in the TME and thus lead to novel concepts for the treatment or prevention of HCC.