Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma.
Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma.
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DOI：
10.1002/hep.26898
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发表时间：
2014-04
期刊：
影响因子：
13.5
通讯作者：
Tanabe, Kenneth K.
中科院分区：
文献类型：
--
作者：
Fuchs, Bryan C.;Hoshida, Yujin;Fujii, Tsutomu;Wei, Lan;Yamada, Suguru;Lauwers, Gregory Y.;McGinn, Christopher M.;DePeralta, Danielle K.;Chen, Xintong;Kuroda, Toshihiko;Lanuti, Michael;Schmitt, Anthony D.;Gupta, Supriya;Crenshaw, Andrew;Onofrio, Robert;Taylor, Bradley;Winckler, Wendy;Bardeesy, Nabeel;Caravan, Peter;Golub, Todd R.;Tanabe, Kenneth K.
肝细胞癌（HCC）是美国癌症相关死亡率增长最快的原因。由于缺乏可行的治疗方案，肝癌，预防高风险患者已被提出作为一种替代策略。肝癌的主要危险因素是肝硬化，有几条证据表明表皮生长因子（EGF）参与肝硬化的进展和肝癌的发展。因此，我们研究了表皮生长因子受体（EGFR）抑制剂厄洛替尼对肝纤维化和肝细胞转化的影响，在三种不同的动物模型进行性肝硬化-大鼠模型诱导的重复，低剂量注射二乙基亚硝胺（DEN），小鼠模型诱导的四氯化碳（CCl 4）和大鼠模型诱导的胆管结扎（BDL）。厄洛替尼可降低肝星状细胞（HSC）中EGFR的磷酸化，并减少活化HSC的总数。厄洛替尼还降低肝细胞增殖和肝损伤。与所有这些发现相一致，EGFR信号传导的药理学抑制有效地防止了一些动物中肝硬化和纤维化消退的进展。此外，通过减轻潜在的肝脏疾病，厄洛替尼阻断了HCC的发展，并且其治疗功效可以用先前报道的预测人类肝硬化患者中HCC风险的基因表达特征来监测。这些数据表明，用FDA批准的抑制剂抑制EGFR为减少高风险肝硬化患者的纤维化和预防HCC提供了一种有希望的治疗方法，这些患者可以通过基因表达特征进行识别和监测。
Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer-related mortality in the United States. Because of the lack of viable treatment options for HCC, prevention in high risk patients has been proposed as an alternative strategy. The main risk factor for HCC is cirrhosis and several lines of evidence implicate epidermal growth factor (EGF) in the progression of cirrhosis and development of HCC. We therefore examined the effects of the EGF receptor (EGFR) inhibitor erlotinib on liver fibrogenesis and hepatocellular transformation in three different animal models of progressive cirrhosis – a rat model induced by repeated, low dose injections of diethylnitrosamine (DEN), a mouse model induced by carbon tetrachloride (CCl4) and a rat model induced by bile duct ligation (BDL). Erlotinib reduced EGFR phosphorylation in hepatic stellate cells (HSC), and reduced the total number of activated HSC. Erlotinib also decreased hepatocyte proliferation and liver injury. Consistent with all these findings, pharmacological inhibition of EGFR signaling effectively prevented the progression of cirrhosis and regressed fibrosis in some animals. Moreover, by alleviating the underlying liver disease, erlotinib blocked the development of HCC and its therapeutic efficacy could be monitored with a previously reported gene expression signature predictive of HCC risk in human cirrhosis patients. These data suggest that EGFR inhibition with FDA-approved inhibitors presents a promising therapeutic approach for reduction of fibrogenesis and prevention of HCC in high risk cirrhosis patients who can be identified and monitored by gene expression signatures.
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影响因子：
13.5
作者：
Perugorria, Maria J.;Latasa, M. Ujue;Avila, Matias A.
通讯作者：
Avila, Matias A.
DOI：
10.1073/pnas.1222878110
发表时间：
2013-02-26
影响因子：
11.1
作者：
Seok, Junhee;Warren, H. Shaw;Tompkins, Ronald G.
通讯作者：
Tompkins, Ronald G.
影响因子：
3.8
作者：
Falleti, Edmondo;Cmet, Sara;Toniutto, Pierluigi
通讯作者：
Toniutto, Pierluigi
影响因子：
25.7
作者：
Blivet-Van Eggelpoel, Marie-Jose;Chettouh, Hamza;Desbois-Mouthon, Christele
通讯作者：
Desbois-Mouthon, Christele
DOI：
10.1056/nejmoa0804525
发表时间：
2008-11-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hoshida Y;Villanueva A;Kobayashi M;Peix J;Chiang DY;Camargo A;Gupta S;Moore J;Wrobel MJ;Lerner J;Reich M;Chan JA;Glickman JN;Ikeda K;Hashimoto M;Watanabe G;Daidone MG;Roayaie S;Schwartz M;Thung S;Salvesen HB;Gabriel S;Mazzaferro V;Bruix J;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR