Antiangiogenic and Antitumor Activities of Aflibercept, a Soluble VEGF Receptor-1 and -2, in a Mouse Model of Hepatocellular Carcinoma.
Antiangiogenic and Antitumor Activities of Aflibercept, a Soluble VEGF Receptor-1 and -2, in a Mouse Model of Hepatocellular Carcinoma.
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DOI：
10.1016/j.neo.2016.05.001
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发表时间：
2016-07
期刊：
影响因子：
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通讯作者：
Yano H
中科院分区：
文献类型：
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作者：
Torimura T;Iwamoto H;Nakamura T;Abe M;Ikezono Y;Wada F;Sakaue T;Masuda H;Hashimoto O;Koga H;Ueno T;Yano H
背景与目的：阿柏西普在美国被称为ziv-aflibercept，是血管内皮生长因子（VEGF）受体-1和-2的可溶性诱饵受体，已知可抑制VEGF和胎盘生长因子（PlGF）与VEGF受体-1和-2的结合。在这里，我们分析了阿柏西普在小鼠肝癌模型中的抗肿瘤作用机制。方法：在体外研究中，我们确定了阿柏西普对人脐静脉细胞（HUVEC）增殖和骨髓（BM）细胞分化为内皮祖细胞（EPC）的影响。在体内实验中，将阿柏西普腹腔注射到荷瘤小鼠的肝癌细胞中，评估其对肿瘤生长和BM细胞向肿瘤组织迁移的抑制作用。结果：阿柏西普抑制 HUVEC 中 VEGF 受体-1 和 -2 的磷酸化，并以剂量依赖性抑制 VEGF 诱导的 HUVEC 增殖。它抑制BM细胞向EPC的分化以及BM细胞向肿瘤组织的迁移。它还可以抑制肿瘤生长并延长荷瘤小鼠的生存时间，且无副作用。在肿瘤组织中，阿柏西普上调缺氧诱导因子1-α、VEGF、PlGF、成纤维细胞生长因子-2、血小板衍生生长因子-BB和转化生长因子-α的表达，并降低微血管密度。它还降低了非癌性肝组织中的肝窦密度。结论：我们的结果证明阿柏西普在肝细胞癌小鼠模型中具有有效的抗肿瘤活性。这些作用是通过抑制新血管形成来介导的，而新血管形成是通过抑制内皮细胞增殖、EPC 分化和 BM 细胞迁移到肿瘤组织而引起的。
BACKGROUND & AIM: Aflibercept known as ziv-aflibercept in the United States is a soluble decoy receptor of both vascular endothelial growth factor (VEGF) receptor-1 and -2 known to inhibit the binding of VEGF and placental growth factor (PlGF) to VEGF receptor-1 and -2. Here, we analyzed the mechanisms of the antitumor effects of aflibercept in mouse hepatoma models. METHODS: In in vitro studies, we determined the effects of aflibercept on human umbilical vein cell (HUVEC) proliferation and bone marrow (BM) cell differentiation to endothelial progenitor cells (EPCs). In in vivo experiments, aflibercept was injected intraperitoneally in hepatoma cell tumor-bearing mice, and its inhibitory effects on tumor growth and BM cell migration to tumor tissues were evaluated. RESULTS: Aflibercept suppressed phosphorylation of VEGF receptor-1 and -2 in HUVEC and dose-dependently inhibited VEGF-induced HUVEC proliferation. It suppressed the differentiation of BM cells to EPCs and migration of BM cells to tumor tissues. It also suppressed tumor growth and prolonged survival time of tumor-bearing mice without side effects. In tumor tissues, aflibercept upregulated the expression of hypoxia inducible factor1-α, VEGF, PlGF, fibroblast growth factor-2, platelet derived growth factor-BB, and transforming growth factor-α and reduced microvascular density. It also reduced sinusoidal density in noncancerous liver tissues. CONCLUSIONS: Our results demonstrated potent antitumor activity for aflibercept in a mouse model of hepatocellular carcinoma. These effects were mediated through inhibition of neovascularization, caused by inhibition of endothelial cell proliferation, EPC differentiation, and BM cell migration to tumor tissues.