Akagi M, Kawaguchi M, Liu W, McCarty M F, Takeda A, Fan F, Stoeltzing O, Parikh A A, Jung Y D, Bucana C D, Mansfield P F, Hicklin D J, Ellis L M
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA.
Br J Cancer. 2003 Mar 10;88(5):796-802. doi: 10.1038/sj.bjc.6600811.
The epidermal growth factor receptor (EGF-R) pathway plays a pivotal role in the progression of human gastric cancer. The angiogenic factor vascular endothelial growth factor (VEGF) has been shown to be induced by EGF in various cancer cell lines. Neuropilin-1 (NRP-1) acts as a coreceptor for VEGF-165 and increases its affinity for VEGF receptor 2 (VEGFR-2) in endothelial cells. Furthermore, NRP-1 has been found to be expressed by tumour cells and has been shown to enhance tumour angiogenesis and growth in preclinical models. We examined the expression of NRP-1 mRNA and EGF-R protein in seven human gastric cancer cell lines. NRP-1 expression was expressed in five of seven cell lines, and EGF-R expression closely mirrored NRP-1 expression. Moreover, in EGF-R-positive NCI-N87 and ST-2 cells, EGF induced both NRP-1 and VEGF mRNA expression. C225, a monoclonal antibody to EGF-R, blocked EGF-induced NRP-1 and VEGF expression in NCI-N87 cells in a dose-dependent manner. The treatment of NCI-N87 cells with EGF resulted in increases in phosphorylation of Erk1/2, Akt, and P38. Blockade of the Erk, phosphatidylinositol-3 kinase/Akt, or P38 pathways in this cell line prevented EGF induction of NRP-1 and VEGF. These results suggest that regulation of NRP-1 expression in human gastric cancer is intimately associated with the EGF/EGF-R system. Activation of EGF-R might contribute to gastric cancer angiogenesis by a mechanism that involves upregulation of VEGF and NRP-1 expression via multiple signalling pathways.
表皮生长因子受体（EGF-R）通路在人类胃癌进展中起关键作用。血管生成因子血管内皮生长因子（VEGF）已被证明在多种癌细胞系中可由EGF诱导产生。神经纤毛蛋白-1（NRP-1）作为VEGF-165的共受体，可增加其在内皮细胞中对VEGF受体2（VEGFR-2）的亲和力。此外，已发现NRP-1在肿瘤细胞中表达，并在临床前模型中显示可促进肿瘤血管生成和生长。我们检测了7种人类胃癌细胞系中NRP-1 mRNA和EGF-R蛋白的表达。7种细胞系中有5种表达NRP-1，且EGF-R表达与NRP-1表达密切相关。此外，在EGF-R阳性的NCI-N87和ST-2细胞中，EGF可诱导NRP-1和VEGF mRNA表达。EGF-R单克隆抗体C225可剂量依赖性地阻断EGF诱导的NCI-N87细胞中NRP-1和VEGF表达。用EGF处理NCI-N87细胞导致Erk1/2、Akt和P38磷酸化增加。阻断该细胞系中的Erk、磷脂酰肌醇-3激酶/Akt或P38通路可阻止EGF对NRP-1和VEGF的诱导。这些结果表明，人类胃癌中NRP-1表达的调控与EGF/EGF-R系统密切相关。EGF-R的激活可能通过涉及经由多种信号通路上调VEGF和NRP-1表达的机制促进胃癌血管生成。
