Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Mol Cancer Ther. 2011 May;10(5):850-60. doi: 10.1158/1535-7163.MCT-10-0917. Epub 2011 Mar 1.
The epithelial to mesenchymal transition (EMT) of malignant hepatocytes is a crucial event in hepatocellular carcinoma (HCC) progression and recurrence. We aimed to establish a human model of EMT to examine drug efficacy and specificity in HCC progression. Human HCC cell populations were characterized by immunofluorescence analysis, migration and invasion assays, array comparative genomic hybridization, whole-genome expression profiling, and promoter methylation. Therapeutic agents clinically used against HCC were examined for efficacy by determination of IC(50) values. We show that liver cancer cell lines exhibited either an epithelial or mesenchymal phenotype of which the latter showed strong migratory and invasive abilities in vitro. The common cellular origin of both cell types indicated that mesenchymal HCC cells have been derived from epithelial hepatocytes through EMT in the HCC patient. Drug exposure of mesenchymal HCC cells showed higher resistance to the targeted therapeutic agents sorafenib and erlotinib as compared to epithelial HCC cells, which were slightly more resistant to cytostatic drugs. Most remarkably, combined treatment with doxorubicin and sorafenib caused increased susceptibility of both HCC cell types resulting in enhanced drug efficacy. Taken together, this EMT model of human HCC allows the identification of molecular mechanisms and the assessment of therapeutic drug efficacy during liver cancer progression in preclinical studies.
上皮间质转化（EMT）是肝癌（HCC）进展和复发过程中的关键事件。我们旨在建立人类 EMT 模型，以研究 HCC 进展过程中药物的疗效和特异性。通过免疫荧光分析、迁移和侵袭实验、阵列比较基因组杂交、全基因组表达谱分析和启动子甲基化分析，对人 HCC 细胞群体进行了特征描述。通过测定 IC50 值，对临床上用于治疗 HCC 的治疗药物进行了疗效检测。我们发现肝癌细胞系表现出上皮或间质表型，其中后者在体外具有很强的迁移和侵袭能力。这两种细胞类型的共同细胞起源表明，间质 HCC 细胞是通过 EMT 从 HCC 患者的上皮肝细胞中衍生而来的。与上皮 HCC 细胞相比，间充质 HCC 细胞对靶向治疗药物索拉非尼和厄洛替尼的药物暴露显示出更高的耐药性，而对细胞毒性药物的耐药性略高。最显著的是，阿霉素和索拉非尼联合治疗导致两种 HCC 细胞类型的敏感性增加，从而增强了药物疗效。总之，这种人类 HCC 的 EMT 模型允许在临床前研究中鉴定肝癌进展过程中的分子机制和评估治疗药物的疗效。
