VEGF-A/VEGFR-2 信号通路对胰腺癌细胞的运动性起着重要作用。

VEGF-A/VEGFR-2 signaling plays an important role for the motility of pancreas cancer cells.

机构信息

Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.

出版信息

Ann Surg Oncol. 2012 Aug;19(8):2733-43. doi: 10.1245/s10434-011-2181-6. Epub 2011 Dec 30.

DOI:10.1245/s10434-011-2181-6

PMID:22207048

Abstract

BACKGROUND

Pancreatic cancer is one of the most lethal solid tumors. Vascular endothelial growth factor receptors (VEGFRs) are expressed not only by endothelial cells but also by pancreatic cancer cells. VEGFRs might play an important role for the development of pancreatic cancer cells. The purpose of this study was to evaluate the efficacy of VEGF/VEGFR-2-targeted therapy in pancreatic carcinoma.

METHODS

Five pancreatic carcinoma cell lines were used. The expression level of VEGFR-2 of cancer cells was examined by RT-PCR and Western blot. The effects of VEGFs, bevacizumab as an anti-VEGF antibody, sunitinib as a tyrosine kinase inhibitor against VEGFRs, and VEGF-R2 siRNA on the motility activity of pancreatic cancer cells were examined by invasion assay and wound healing assay. The effect of VEGF, bevacizumab, and sunitinib on the phosphorylation of VEGFR-2 and downstream effecter molecules, MAPK and PI3K, was examined by western blot.

RESULTS

Pancreatic cancer cell lines expressed VEGFR-2. VEGF-A significantly increased the motility of pancreas cancer cells, which was inhibited by VEGFR-2 siRNA. Conditioned medium from pancreas cancer cells significantly stimulated the motility of pancreas cancer cells. VEGF/VEGFR inhibitors, bevacizumab and sunitinib, significantly decreased the motility of pancreas cancer cells. VEGFR-2 phosphorylation level of pancreas cancer cells was increased by VEGF-A. Bevacizumab and sunitinib decreased the level of VEGFR-2 phosphorylation, p-ERK, and p-Akt expression. VEGF-A decreased zonula occludens (ZO-1) or ZO-2 expression in pancreas cancer cells.

CONCLUSIONS

VEGF-A/VEGFR-2 signaling plays an important role in inducing invasion and migration of pancreatic cancer cells.

摘要

背景

胰腺癌是最致命的实体肿瘤之一。血管内皮生长因子受体 (VEGFRs) 不仅在血管内皮细胞中表达，也在胰腺癌细胞中表达。VEGFRs 可能在胰腺癌细胞的发展中发挥重要作用。本研究旨在评估 VEGF/VEGFR-2 靶向治疗在胰腺癌中的疗效。

方法

使用了 5 种胰腺癌细胞系。通过 RT-PCR 和 Western blot 检测癌细胞中 VEGFR-2 的表达水平。通过侵袭实验和划痕愈合实验检测 VEGF、bevacizumab（一种抗 VEGF 抗体）、sunitinib（一种 VEGFRs 酪氨酸激酶抑制剂）和 VEGF-R2 siRNA 对胰腺癌细胞迁移活性的影响。通过 Western blot 检测 VEGF、bevacizumab 和 sunitinib 对 VEGFR-2 及其下游效应分子 MAPK 和 PI3K 磷酸化的影响。

结果

胰腺癌细胞系表达 VEGFR-2。VEGF-A 显著增加胰腺癌细胞的迁移能力，VEGF-R2 siRNA 可抑制其迁移能力。胰腺癌细胞的条件培养基显著刺激胰腺癌细胞的迁移能力。VEGF/VEGFR 抑制剂 bevacizumab 和 sunitinib 显著降低胰腺癌细胞的迁移能力。VEGF-A 可增加胰腺癌细胞 VEGFR-2 磷酸化水平。Bevacizumab 和 sunitinib 降低 VEGFR-2 磷酸化、p-ERK 和 p-Akt 的表达水平。VEGF-A 可降低胰腺癌细胞中 zonula occludens (ZO-1) 或 ZO-2 的表达。