A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells
A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells
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DOI：
10.1002/ijc.29097
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发表时间：
2015-02-15
影响因子：
6.4
通讯作者：
Fabregat, Isabel
中科院分区：
文献类型：
--
作者：
Fernando, Joan;Malfettone, Andrea;Fabregat, Isabel
多激酶抑制剂索拉非尼是晚期肝细胞癌（HCC）唯一有效的药物。然而，不同患者的反应不同，有效性只意味着延迟。我们最近描述了索拉非尼使HCC细胞对凋亡敏感。在这项工作中，我们探索了六种不同的肝肿瘤细胞系对这种药物的反应，以确定一种表型特征，这种特征可能预测HCC患者缺乏反应。结果表明，在体外研究中，表现出间充质样表型、对转化生长因子β (TGF-)抑制作用有抗性、干细胞标记物CD44高表达的肝肿瘤细胞对索拉非尼诱导的细胞死亡具有难治性，这与人类HCC裸鼠异种移植模型中对索拉非尼缺乏反应有关。相比之下，在体外和体内，表达干细胞相关蛋白EpCAM或CD133的上皮样细胞对索拉非尼诱导的凋亡都很敏感。在HCC细胞系中发现TGF-通路与CD44表达上调的间充质样表型的获得之间存在串扰。CD44在间充质样细胞中的靶向敲除表明CD44在保护HCC细胞免受索拉非尼诱导的凋亡中起积极作用。然而，CD44的作用需要TGF诱导的间充质背景，因为CD44在上皮样HCC细胞中的过度表达不足以损害索拉非尼诱导的细胞死亡。总之，与TGF-通路激活相关的间质特征和CD44的表达可能预测HCC患者对索拉非尼缺乏反应。有什么新鲜事吗?索拉非尼仍然是晚期肝细胞癌（HCC）的标准治疗，尽管患者的反应存在显著差异。根据这项研究，对索拉非尼缺乏反应可以通过肝脏肿瘤细胞的某些表型特征，特别是TGF-ss通路的激活，间充质表型和CD44的表达来预测。相比之下，对索拉非尼诱导的细胞凋亡的敏感性与上皮样细胞中干细胞相关蛋白EpCAM或CD133的表达和间充质样细胞中CD44的敲低有关。研究结果表明，靶向CD44可能是与索拉非尼治疗联合使用的一种有价值的策略。
The multikinase inhibitor sorafenib is the only effective drug in advanced cases of hepatocellular carcinoma (HCC). However, response differs among patients and effectiveness only implies a delay. We have recently described that sorafenib sensitizes HCC cells to apoptosis. In this work, we have explored the response to this drug of six different liver tumor cell lines to define a phenotypic signature that may predict lack of response in HCC patients. Results have indicated that liver tumor cells that show a mesenchymal-like phenotype, resistance to the suppressor effects of transforming growth factor beta (TGF-) and high expression of the stem cell marker CD44 were refractory to sorafenib-induced cell death in in vitro studies, which correlated with lack of response to sorafenib in nude mice xenograft models of human HCC. In contrast, epithelial-like cells expressing the stem-related proteins EpCAM or CD133 were sensitive to sorafenib-induced apoptosis both in vitro and in vivo. A cross-talk between the TGF- pathway and the acquisition of a mesenchymal-like phenotype with up-regulation of CD44 expression was found in the HCC cell lines. Targeted CD44 knock-down in the mesenchymal-like cells indicated that CD44 plays an active role in protecting HCC cells from sorafenib-induced apoptosis. However, CD44 effect requires a TGF--induced mesenchymal background, since the only overexpression of CD44 in epithelial-like HCC cells is not sufficient to impair sorafenib-induced cell death. In conclusion, a mesenchymal profile and expression of CD44, linked to activation of the TGF- pathway, may predict lack of response to sorafenib in HCC patients.What's new? Sorafenib remains the standard of care for advanced hepatocellular carcinoma (HCC), despite marked variability in patient response. According to this study, a lack of response to sorafenib may be predicted by certain phenotypic signatures of liver tumor cells, specifically activation of the TGF-ss pathway, a mesenchymal phenotype, and expression of CD44. By contrast, sensitivity to sorafenib-induced apoptosis is associated with expression of the stem-related proteins EpCAM or CD133 in epithelial-like cells and knockdown of CD44 in mesenchymal-like cells. The findings suggest that CD44 targeting could be a valuable strategy to deploy in combination with sorafenib therapy.