In hepatocellular carcinoma (HCC), a subset of cells defined by high CD44 and CD133 expression has been reported to possess cancer stem-like cell (CSC) characteristics and to be associated with a poor prognosis. Since the approval of the multikinase inhibitor, lenvatinib, for patients with unresectable HCC, two such inhibitors (sorafenib and lenvatinib) have been employed as first-line systemic chemotherapeutics for these patients. Based on differences in the kinase-affinity profiles between these two drugs, evidence has suggested that both exert different effects on HCC, although these differences are not fully characterized. In this study, using in vitro and a preclinical in vivo xenograft mouse model, we showed that lenvatinib alone (not sorafenib or the cytotoxic agent, 5-fluorouracil) diminished CD44High/CD133High CSCs in HCC. Furthermore, western blotting and reverse transcriptase-polymerase chain reaction analysis revealed that the expression of fibroblast growth factor receptor (FGFR)-1-4 differed between CD44High/CD133High CSCs and control cells. Analysis of the effects of selective FGFR inhibitors and FGFR small interfering RNAs on CSCs in HCC revealed that lenvatinib diminished CSCs in HCC by inhibiting FGFR1-3 signaling, however, FGFR4 signaling was not impacted. Finally, we showed that FGF2 and FGF19 were involved in maintaining CD44High/CD133High CSCs in HCC, potentially, via FGFR1-3. The findings provide novel mechanistic insights into the effects of lenvatinib on CSCs in HCC and provide clues for developing effective targeted therapies against CSCs in HCC.

中文翻译：

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乐伐替尼通过抑制 FGFR1-3 信号而不是 FGFR4 信号来抑制 HCC 中的癌症干细胞样细胞。

在肝细胞癌 (HCC) 中，据报道由高 CD44 和 CD133 表达定义的细胞亚群具有癌症干细胞样细胞 (CSC) 特征并与不良预后相关。自从多激酶抑制剂乐伐替尼获批用于不可切除的 HCC 患者以来，两种此类抑制剂（索拉非尼和乐伐替尼）已被用作这些患者的一线全身化疗药物。基于这两种药物在激酶亲和性方面的差异，有证据表明这两种药物对 HCC 产生不同的影响，尽管这些差异尚未完全表征。在这项研究中，我们使用体外和临床前体内异种移植小鼠模型，表明单独使用乐伐替尼（不是索拉非尼或细胞毒性剂 5-氟尿嘧啶）可减少 HCC 中的 CD44High/CD133High CSC。此外，蛋白质印迹和逆转录酶-聚合酶链反应分析显示，成纤维细胞生长因子受体 (FGFR)-1-4 的表达在 CD44High/CD133High CSC 和对照细胞之间存在差异。选择性 FGFR 抑制剂和 FGFR 小干扰 RNA 对 HCC 中 CSC 的影响分析表明，乐伐替尼通过抑制 FGFR1-3 信号减少 HCC 中的 CSC，然而，FGFR4 信号不受影响。最后，我们表明 FGF2 和 FGF19 可能通过 FGFR1-3 参与维持 HCC 中的 CD44High/CD133High CSC。这些发现为乐伐替尼对 HCC 中 CSC 的影响提供了新的机制见解，并为开发针对 HCC 中 CSC 的有效靶向疗法提供了线索。