Targeting Jak/Stat pathway as a therapeutic strategy against SP/CD44+tumorigenic cells in Akt/β-catenin-driven hepatocellular carcinoma
Targeting Jak/Stat pathway as a therapeutic strategy against SP/CD44+tumorigenic cells in Akt/β-catenin-driven hepatocellular carcinoma
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DOI：
10.1016/j.jhep.2019.08.035
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发表时间：
2020-01-01
影响因子：
25.7
通讯作者：
Chow, Edward Kai-Hua
中科院分区：
文献类型：
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作者：
Toh, Tan Boon;Lim, Jhin Jieh;Chow, Edward Kai-Hua
背景与目的：肝切除、肝移植辅以放化疗是治疗肝细胞癌的主要手段，但肝内复发和肝内转移频繁，5年生存率较低。目前只有索拉非尼和lenvatinib被批准用于晚期未切除肝癌的一线治疗，但它们产生的生存益处不大。因此，有必要寻找新的治疗靶点来改进目前的肝癌治疗模式。方法：通过流体动力转染法建立AKT1和β-连环蛋白(CTNNBI)癌基因的肝癌模型。用侧群(SP)和CD44表面标志物通过流式细胞术分离具有干细胞特性的癌细胞。结果：在14.4%的肝细胞癌患者中发现Wnt/β-catenin和Akt/mTor信号通路的共激活。更重要的是，这些患者的存活率比那些单独激活Wnt/β-catenin或Akt/mTOR通路的患者更差，这表明了我们研究的临床相关性。此外，我们观察到Akt/β-catenin肿瘤细胞亚群通过SP分析和肿瘤干细胞样标记物CD44的表达鉴定具有干/祖细胞样特性，这可能与肿瘤的自我更新和耐药有关。结论：在Akt/β-catenin诱导的肝细胞癌中，我们发现了一组具有干/祖细胞特性的肿瘤起始细胞亚群，Jak/Stat通路的抑制剂可以有效地靶向该细胞亚群，说明抑制Jak/Stat通路可能是克服耐药性和有效治疗Akt/β-catenin驱动的肝癌的一种替代方法。部分原因是对那些患有更严重疾病的人缺乏有效的治疗选择。在这项研究中，我们在小鼠肝细胞癌模型中鉴定了一类具有干细胞样特性的癌细胞亚群，这对肿瘤的维持和生长至关重要。通过进一步的实验，我们证明了Jak/Stat通路是一个很有前途的肝细胞癌的治疗靶点。(C)2019年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: Hepatic resection and liver transplantation with adjuvant chemo- and radiotherapy are the mainstay of hepatocellular carcinoma (HCC) treatment, but the 5-year survival rate remains poor because of frequent recurrence and intrahepatic metastasis. Only sorafenib and lenvatinib are currently approved for the first-line treatment of advanced, unresected HCC, but they yield modest survival benefits. Thus, there is a need to identify new therapeutic targets to improve current HCC treatment modalities.Methods: The HCC tumor model was generated by hydrodynamic transfection of AKT1 and beta-catenin (CTNNBI) oncogenes. Cancer cells with stemness properties were characterized following isolation using side population (SP) and CD44 surface markers by flow cytometry. The effect of Jak/Stat inhibitors was analyzed in vitro by using tumorsphere culture and in vivo using an allograft mouse model.Results: Co-activation of both Wnt/beta-catenin and Akt/mTOR pathways was found in 14.4% of our HCC patient cohort. More importantly, these patients showed poorer survival than those with either Wnt/beta-catenin or Akt/mTOR pathway activation alone, demonstrating the clinical relevance of our study. In addition, we observed that Akt/beta-catenin tumors contained a subpopulation of cells with stem/progenitor-like characteristics identified through SP analysis and expression of the cancer stem cell-like marker CD44, which may contribute to tumor self-renewal and drug resistance. Consequently, we identified small molecule inhibitors of the Jak/Stat pathway that demonstrated efficacy in mitigating tumor proliferation and formation in Akt/beta-catenin-driven HCC.Conclusions: In conclusion, we have shown that Akt/beta-catenin tumors contain a subpopulation of tumor-initiating cells with stem/progenitor-like characteristics which can be effectively targeted with inhibitors of the Jak/Stat pathway, demonstrating that inhibition of the Jak/Stat pathway could be an alternative method to overcome drug resistance and effectively treat Akt/beta-catenin-driven HCC tumors.Lay summary: The prognosis for patients with hepatocellular carcinoma is poor, partly because of the lack of effective treatment options for those with more advanced disease. In this study, we identified a subpopulation of cancer cells with stem cell-like properties that were critical for tumor maintenance and growth in a mouse model of hepatocellular carcinoma. Through further experiments, we demonstrated that the Jak/Stat pathway is a promising therapeutic target in hepatocellular carcinoma. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.