Abstract
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.
Highlights
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma
We found that the phosphorylation levels of vascular endothelial growth factor receptor 2 (VEGFR2) and AKT were significantly reduced in the anlotinib group compared with the control group
We found that anlotinib stopped the proliferation, migration, and invasion effects in the ICC cells that were caused by recombinant human vascular endothelial growth factor (VEGF); siVEGFR2 decreased the effects of anlotinib in the ICC cells (Fig. 6a–c)
Summary
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma. The wound-healing assays revealed that anlotinib effectively inhibited the migration of HCCC9810 cells (100.00 ± 4.14 for control vs 34.32 ± 6.71 for anlotinib, P < 0.01); similar results were observed for the RBE cell line (100.00 ± 5.21 vs 21.84 ± 5.73, respectively, P < 0.01; Fig. 2a).
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