Torimura Takuji, Iwamoto Hideki, Nakamura Toru, Abe Mitsuhiko, Ikezono Yu, Wada Fumitaka, Sakaue Takahiko, Masuda Hiroshi, Hashimoto Osamu, Koga Hironori, Ueno Takato, Yano Hirohisa
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; Liver Cancer Division, Research Center for Innovative Cancer Therapy, Kurume, Japan.
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
Neoplasia. 2016 Jul;18(7):413-24. doi: 10.1016/j.neo.2016.05.001.
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.
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.
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.
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.
阿柏西普在美国被称为阿瓦斯汀，是一种可溶性诱饵受体，可同时作用于血管内皮生长因子（VEGF）受体-1和-2，已知其能抑制VEGF和胎盘生长因子（PlGF）与VEGF受体-1和-2的结合。在此，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。
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）细胞向内皮祖细胞（EPC）分化的影响。在体内实验中，将阿柏西普腹腔注射到荷肝癌细胞的小鼠体内，并评估其对肿瘤生长和BM细胞向肿瘤组织迁移的抑制作用。
阿柏西普抑制HUVEC中VEGF受体-1和-2的磷酸化，并剂量依赖性地抑制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窦状隙密度。
我们的结果证明阿柏西普在小鼠肝细胞癌模型中具有强大的抗肿瘤活性。这些作用是通过抑制新生血管形成介导的，新生血管形成是由抑制内皮细胞增殖、EPC分化和BM细胞向肿瘤组织迁移引起的。
