Sorafenib Enriches Epithelial Cell Adhesion Molecule-Positive Tumor Initiating Cells and Exacerbates a Subtype of Hepatocellular Carcinoma Through TSC2-AKT Cascade
Sorafenib Enriches Epithelial Cell Adhesion Molecule-Positive Tumor Initiating Cells and Exacerbates a Subtype of Hepatocellular Carcinoma Through TSC2-AKT Cascade
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索拉非尼通过 TSC2-AKT 级联富集上皮细胞粘附分子阳性肿瘤起始细胞并加剧肝细胞癌的亚型
DOI：
10.1002/hep.28117
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发表时间：
2015-12-01
期刊：
影响因子：
13.5
通讯作者：
Xie, Dong
中科院分区：
文献类型：
--
作者：
Guan, Dong-Xian;Shi, Jie;Xie, Dong
索拉非尼是一种特异性三磷酸腺苷竞争性RAF抑制剂，用作晚期肝细胞癌（HCC）的一线治疗。然而，反应是可变的，反映了疾病的异质性，而耐药机制仍然知之甚少。在这里，我们报告索拉非尼治疗可以加剧患者来源的异种移植物和细胞系来源的异种移植物中的疾病进展，并且药物的治疗效果与上皮细胞粘附分子阳性细胞的比例呈负相关，上皮细胞粘附分子阳性细胞可能是HCC中的肿瘤起始细胞。TSC 2-AKT级联介导这种索拉非尼抗性。索拉非尼治疗后，TSC 1/2复合物的形成增强，导致AKT磷酸化增加，这有助于上皮细胞粘附分子阳性细胞中“干性”相关基因的上调和致瘤性的增强。TSC 2的表达与索拉非尼临床治疗的预后呈负相关。此外，全反式维甲酸降低AKT活性，减少索拉非尼富集的上皮细胞粘附分子阳性细胞群，并增强索拉非尼在患者来源的异种移植模型中的治疗作用。结论：我们的发现表明HCC的亚型不适合索拉非尼治疗;这种对索拉非尼的抗性可以通过TSC 2的状态和诱导肿瘤起始细胞分化的试剂（例如，全反式维甲酸）应该改善这种HCC亚型的预后。
Sorafenib is a specific adenosine triphosphate-competitive RAF inhibitor used as a first-line treatment of advanced hepatocellular carcinoma (HCC). However, the responses are variable, reflecting heterogeneity of the disease, while the resistance mechanism remains poorly understood. Here, we report that sorafenib treatment can exacerbate disease progression in both patient-derived xenografts and cell line-derived xenografts and that the therapeutic effect of the drug inversely covaries to the ratio of epithelial cell adhesion molecule-positive cells, which may be tumor initiating cells in HCC. The TSC2-AKT cascade mediates this sorafenib resistance. In response to sorafenib treatment, formation of the TSC1/2 complex is enhanced, causing increased phosphorylation of AKT, which contributes to up-regulation of "stemness"-related genes in epithelial cell adhesion molecule-positive cells and enhancement of tumorigenicity. The expression of TSC2 negatively correlated with prognosis in clinical sorafenib therapy. Furthermore, all-trans retinoic acid decreased AKT activity, reduced the epithelial cell adhesion molecule-positive cell population enriched by sorafenib, and potentiated the therapeutic effect of sorafenib in the patient-derived xenograft model. Conclusion: Our findings suggest that a subtype of HCC is not suitable for sorafenib therapy; this resistance to sorafenib can be predicted by the status of TSC2, and agents inducing differentiation of tumor initiating cells (e.g., all-trans retinoic acid) should improve the prognosis of this subtype of HCC.