Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR1-3 signaling, but not FGFR4 signaling
Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR1-3 signaling, but not FGFR4 signaling
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DOI：
10.1093/carcin/bgaa049
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发表时间：
2021-01-01
期刊：
影响因子：
4.7
通讯作者：
Sakamoto, Naoya
中科院分区：
文献类型：
--
作者：
Shigesawa, Taku;Maehara, Osamu;Sakamoto, Naoya
在肝细胞癌（HCC）中，由高CD 44和CD 133表达定义的细胞亚群已被报道具有癌症干细胞样细胞（CSC）特征，并与不良预后相关。自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。基于这两种药物之间的激酶亲和力谱的差异，有证据表明两者对肝癌产生不同的影响，尽管这些差异尚未得到充分表征。在这项研究中，使用体外和临床前体内异种移植小鼠模型，我们发现乐伐替尼单独（而不是索拉非尼或细胞毒性药物5-氟尿嘧啶）减少了HCC中的CD 44（Hi）（gh）/CD 133（High）CSC。此外，蛋白质印迹和逆转录-聚合酶链反应分析揭示成纤维细胞生长因子受体（FGFR）-1-4的表达在CD 44（Hi）（gh）/CD 133（High）CSC和对照细胞之间不同。选择性FGFR抑制剂和FGFR小干扰RNA对HCC中CSC的影响分析显示，乐伐替尼通过抑制FGFR 1 -3信号传导减少HCC中的CSC，但FGFR 4信号传导不受影响。最后，我们发现FGF 2和FGF 19可能通过FGFR 1 -3参与维持HCC中的CD 44（Hi）（gh）/CD 133（High）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的有效靶向治疗提供了线索。
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 CD44(Hi)(gh)/CD133(High) 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 CD44(Hi)(gh)/CD133(High) 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 CD44(Hi)(gh)/CD133(High) 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.