Autocrine VEGF signaling promotes cell proliferation through a PLC-dependent pathway and modulates Apatinib treatment efficacy in gastric cancer.
Autocrine VEGF signaling promotes cell proliferation through a PLC-dependent pathway and modulates Apatinib treatment efficacy in gastric cancer.
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自分泌 VEGF 信号通过 PLC 依赖性途径促进细胞增殖并调节阿帕替尼治疗胃癌的疗效
DOI：
10.18632/oncotarget.14467
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发表时间：
2017-02-14
期刊：
影响因子：
--
通讯作者：
Chen M
中科院分区：
文献类型：
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作者：
Lin Y;Zhai E;Liao B;Xu L;Zhang X;Peng S;He Y;Cai S;Zeng Z;Chen M
肿瘤细胞产生血管内皮生长因子（VEGF），其与膜或细胞质VEGF受体（VEGFRs）相互作用以促进以血管生成独立的方式的细胞生长。阿帕替尼是一种高度选择性的VEGFR 2抑制剂，是唯一有效的药物，用于没有其他化疗选择的晚期胃癌（GC）患者。然而，其治疗效果仍存在争议，其背后的机制仍不确定。在这项研究中，我们的目的是研究自分泌VEGF信号在胃癌细胞生长中的作用和阿帕替尼治疗的疗效。采用实时荧光定量PCR、免疫荧光和Western blot方法检测胃癌细胞系中VEGFR 2的表达。胃癌细胞在有或没有重组人VEGF（rhVEGF）、VEGFR 2中和抗体、U 73122、SU 1498和阿帕替尼的情况下施用。裸鼠移植瘤模型。我们发现自分泌VEGF诱导胃癌细胞中VEGFR 2的高表达，促进VEGFR 2的磷酸化，并进一步增强pVEGFR 2的内化。自分泌的VEGF通过增加VEGF mRNA和蛋白表达而自我维持。它通过PLC-ERK 1/2依赖性途径发挥促增殖作用。此外，我们证明了在VEGFR 2过表达的胃癌细胞中，阿帕替尼在体外抑制细胞增殖，并在体内延迟异种移植肿瘤生长。然而，在VEGFR 2低表达胃癌细胞中未观察到这些作用。这些结果表明，在体外和体内，自分泌VEGF信号促进胃癌细胞增殖并增强VEGFR 2过表达胃癌细胞中的阿帕替尼治疗结果。这项研究将使更好地分层胃癌患者的临床治疗决策。
Tumor cells produce vascular endothelial growth factor (VEGF) which interact with the membrane or cytoplasmic VEGF receptors (VEGFRs) to promote cell growth in an angiogenesis-independent fashion. Apatinib, a highly selective VEGFR2 inhibitor, is the only effective drug for patients with terminal gastric cancer (GC) who have no other chemotherapeutic options. However, its treatment efficacy is still controversy and the mechanism behind remains undetermined. In this study, we aimed to investigate the role of autocrine VEGF signaling in the growth of gastric cancer cells and the efficacy of Apatinib treatment. The expression of phosphor VEGFR2 in gastric cancer cell lines was determined by real-time PCR, immunofluorescence, and Western blot. The gastric cancer cells were administrated with or without recombination human VEGF (rhVEGF), VEGFR2 neutralizing antibody, U73122, SU1498, and Apatinib. The nude mice were used for xenograft tumor model. we found that autocrine VEGF induced high VEGFR2-expression, promoted phosphorylation of VEGFR2, and further enhanced internalization of pVEGFR2 in gastric cancer cells. The autocrine VEGF was self-sustained through increasing VEGF mRNA and protein expression. It exerted pro-proliferative effect through a PLC-ERK1/2 dependent pathway. Furthermore, we demonstrated that in VEGFR2 overexpressing gastric cancer cells, Apatinib inhibited cell proliferation in vitro and delayed xenograft tumor growth in vivo. However, these effects were not observed in VEGFR2 low expressing gastric cancer cells. These results suggested that autocrine VEGF signaling promotes gastric cancer cell proliferation and enhances Apatinib treatment outcome in VEGFR2 overexpression gastric cancer cells both in vitro and in vivo. This study would enable better stratification of gastric cancer patients for clinical treatment decision.