Anlotinib suppresses tumor progression via blocking the VEGFR2/PI3K/AKT cascade in intrahepatic cholangiocarcinoma
Anlotinib suppresses tumor progression via blocking the VEGFR2/PI3K/AKT cascade in intrahepatic cholangiocarcinoma
复制标题
安罗替尼通过阻断肝内胆管癌中的 VEGFR2/PI3K/AKT 级联抑制肿瘤进展
DOI：
10.1038/s41419-020-02749-7
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发表时间：
2020-07-24
影响因子：
9
通讯作者：
Yang, Xin-Rong
中科院分区：
文献类型：
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作者：
Song, Fei;Hu, Bo;Yang, Xin-Rong
肝内胆管细胞癌是起源于胆管上皮的恶性肿瘤。其特点是起病隐匿，手术后经常复发或转移。目前的化疗和分子靶向治疗仅为ICC患者提供了适度的生存益处。安洛替尼是一种新型的多靶点酪氨酸激酶抑制剂，对多种实体瘤均有良好的抗肿瘤作用。然而，很少有关于安洛替尼相关机制和作为ICC治疗的研究。本研究通过体外实验发现，安洛替尼具有明显的增殖抑制、迁移和侵袭抑制以及细胞周期阻滞作用。安洛替尼治疗影响细胞凋亡和间质-上皮转化的诱导。直接从ICC患者产生的患者来源的异种移植物模型显示，安洛替尼治疗显著阻碍了体内肿瘤生长。我们还使用转录谱分析研究了安洛替尼的作用机制。我们发现，安洛替尼治疗可能主要抑制肿瘤细胞增殖和侵袭，并通过灭活VEGF/PI 3 K/AKT信号通路，通过细胞周期缩短促进细胞凋亡，如这些激酶的磷酸化水平显着降低所证明的。血管内皮生长因子受体2（VEGFR 2）的激活可随后激活PI 3 K/AKT信号传导。我们确定VEGRF 2为安洛替尼的主要靶点。高VEGFR 2表达可能作为一个有前途的指标，用于预测有利的治疗反应。综上所述，这些结果表明，安洛替尼在ICC中具有优异的抗肿瘤活性，主要通过抑制VEGFR 2的磷酸化水平和随后的PIK 3/AKT信号转导的失活。这项工作为将来使用安洛替尼治疗ICC患者提供了证据和理论基础。
Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor derived from bile duct epithelium. Its characteristics include an insidious onset and frequent recurrence or metastasis after surgery. Current chemotherapies and molecular target therapies provide only modest survival benefits to patients with ICC. Anlotinib is a novel multi-target tyrosine kinase inhibitor that has good antitumor effects in a variety of solid tumors. However, there are few studies of anlotinib-associated mechanisms and use as a treatment in ICC. In this study using in vitro experiments, we found that anlotinib had significant effects on proliferation inhibition, migration and invasion restraint, and cell-cycle arrestment. Anlotinib treatment affected induction of apoptosis and the mesenchymal-epithelial transition. Patient-derived xenograft models generated directly from patients with ICC revealed that anlotinib treatment dramatically hindered in vivo tumor growth. We also examined anlotinib's mechanism of action using transcriptional profiling. We found that anlotinib treatment might mainly inhibit tumor cell proliferation and invasion and promote apoptosis via cell-cycle arrestment by inactivating the VEGF/PI3K/AKT signaling pathway, as evidenced by significantly decreased phosphorylation levels of these kinases. The activation of vascular endothelial growth factor receptor 2 (VEGFR2) can subsequently activate PI3K/AKT signaling. We identified VEGRF2 as the main target of anlotinib. High VEGFR2 expression might serve as a promising indicator when used to predict a favorable therapeutic response. Taken together, these results indicated that anlotinib had excellent antitumor activity in ICC, mainly via inhibiting the phosphorylation level of VEGFR2 and subsequent inactivation of PIK3/AKT signaling. This work provides evidence and a rationale for using anlotinib to treat patients with ICC in the future.