HGF derived from cancer-associated fibroblasts promotes vascularization in gastric cancer via PI3K/AKT and ERK1/2 signaling
HGF derived from cancer-associated fibroblasts promotes vascularization in gastric cancer via PI3K/AKT and ERK1/2 signaling
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源自癌症相关成纤维细胞的 HGF 通过 PI3K/AKT 和 ERK1/2 信号传导促进胃癌血管化
DOI：
10.3892/or.2018.6500
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发表时间：
2018-08-01
期刊：
影响因子：
4.2
通讯作者：
Zhang, Jun
中科院分区：
文献类型：
--
作者：
Ding, Xusheng;Xi, Wenqi;Zhang, Jun
癌症相关成纤维细胞（CAF）是肿瘤基质中的主要细胞，在肿瘤进展中发挥关键作用。肝细胞生长因子（HGF）是主要来源于成纤维细胞的细胞因子。在本研究中，我们报道HGF通过增加细胞增殖和迁移，分别显着促进人脐静脉内皮细胞（HUVEC）的血管生成和胃癌细胞的血管生成拟态（VM）形成。此外，重组人 HGF 和来自 CAF 的条件培养基的处理也增加了 HUVEC 和胃癌细胞形成的镶嵌血管。 HGF 中和组获得了相反的结果。根据这些观察结果，我们确定，经 HGF 处理并与 CAF 共培养后，HUVEC 和胃癌细胞中 AKT 和 ERK1/2 的磷酸化上调。 AKT 抑制剂 LY294002 和 ERK1/2 抑制剂 U0126 均降低血管生成和 VM 形成的能力，以及 HGF 诱导的镶嵌血管形成的能力。进行基因集富集分析和相关性分析来证实我们的发现。总之，CAF 衍生的 HGF 通过 PI3K/AKT 和 ERK1/2 信号传导促进胃癌中的血管生成、VM 和镶嵌血管形成，HGF 可能作为癌症抗血管治疗的潜在治疗靶点。
Cancer-associated fibroblasts (CAFs) are predominate cells in tumor stroma and play a key role in tumor progression. Hepatocyte growth factor (HGF) is a cytokine mainly derived from fibroblasts. In the present study, we reported that HGF significantly promoted angiogenesis of human umbilical vein endothelial cells (HUVECs) and vasculogenic mimicry (VM) formation of gastric cancer cells, respectively, by increasing cell proliferation and migration. In addition, mosaic vessels formed by HUVECs and gastric cancer cells were also increased with treatment of recombinant human HGF and conditioned medium from CAFs. The opposite results were achieved in HGF-neutralized groups. In accordance with these observations, we determined that phosphorylation of AKT and ERK1/2 were upregulated in HUVECs and gastric cancer cells with HGF treatment and co-culture with CAFs. Both AKT inhibitor LY294002 and ERK1/2 inhibitor U0126 reduced the ability of angiogenesis and VM formation, as well as mosaic vessel formation induced by HGF. Gene Set Enrichment Analysis and correlation analysis were performed to confirm our findings. In conclusion, CAF-derived HGF promotes angiogenesis, VM and mosaic vessel formation via PI3K/AKT and ERK1/2 signaling in gastric cancer and HGF may serve as a potential therapeutic target for cancer anti-vascular treatment.