Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation
Mammalian target of rapamycin pathway activity in hepatocellular carcinomas of patients undergoing liver transplantation
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DOI：
10.1097/01.tp.0000252780.42104.95
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发表时间：
2007-02-27
期刊：
影响因子：
6.2
通讯作者：
Wacheck, Volker
中科院分区：
文献类型：
--
作者：
Sieghart, Wolfgang;Fuereder, Thorsten;Wacheck, Volker
背景。由于哺乳动物靶向雷帕霉素（mTOR）抑制剂具有抗癌和免疫抑制的双重特性，我们研究了：1)原位肝移植（OLT）患者肝细胞癌（HCC）组织中mTOR通路的激活状态和预后意义；2)RAD001在HCC细胞中的单用和合用疗效。采用免疫组化方法分析166例OLT患者移植hcc的PTEN、p-AKT、p-mTOR、p-p70S6K和p-4EBP-1。在Hep3B和SNU398细胞中检测了RAD001单独或联合阿霉素治疗肝癌的疗效。约40%接受肝细胞癌OLT治疗的患者mTOR通路被激活，但未观察到上游和下游蛋白之间的直接相关性。我们发现mTOR通路蛋白表达对无病生存期（DFS）或总生存期（OS）没有影响。RAD001在体外对肝癌细胞有明显的单药增敏作用。在接受OLT的HCC患者中，40%的mTOR通路活跃，但对DFS或OS没有影响。没有观察到上游和下游蛋白之间的直接相关性，限制了上游蛋白预测mTOR活性的使用。hcc中mTOR通路的激活状态能否预测雷帕霉素衍生物在移植后过程中的抗肿瘤作用，还需要进行前瞻性临床试验。
Background. Because mammalian target of rapamycin (mTOR) inhibitors combine anticancer and immunosuppressive properties we investigated: 1) the activation status and prognostic significance of the mTOR pathway in hepatocellular carcinoma (HCC) tissues of patients undergoing orthotopic liver transplantation (OLT) for HCC and 2) the single and combinatorial efficacy of RAD001 in HCC cells.Methods. PTEN, p-AKT, p-mTOR, p-p70S6K, and p-4EBP-1 were analyzed by immunohistochemistry in explanted HCCs of 166 patients undergoing OLT. Efficacy of RAD001 as mono- and combination therapy with doxorubicin was tested in Hep3B and SNU398 cells.Results. The mTOR pathway is activated in about 40% of patients undergoing OLT for HCC but no direct correlation between up- and downstream proteins was observed. We found no influence of mTOR pathway protein expression on disease free survival (DFS) or overall survival (OS). There was a marked single agent and chemo-sensitizing effect of RAD001 against HCC cells in vitro.Conclusion. The mTOR pathway is active in 40% of patients with HCC undergoing OLT, but has no influence of DFS or OS. No direct correlation was observed between up- and downstream proteins limiting the use of upstream proteins to predict mTOR activity. Prospective clinical trials are needed to test whether the activation status of the mTOR pathway in HCCs predicts the antitumor effect of rapamycin derivative in the posttransplantation course.