Kim Woo Ho, Lee Sun Hee, Jung Myung Hwan, Seo Ji Heun, Kim Jin, Kim Min A, Lee You Mie
Department of Pathology and Surgery, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.
Exp Cell Res. 2009 Aug 1;315(13):2154-64. doi: 10.1016/j.yexcr.2009.04.018. Epub 2009 May 3.
The structure and characteristics of the tumor vasculature are known to be different from those of normal vessels. Neuropilin2 (Nrp2), which is expressed in non-endothelial cell types, such as neuronal or cancer cells, functions as a receptor for both semaphorin and vascular endothelial growth factor (VEGF). After isolating tumor and normal endothelial cells from advanced gastric cancer tissue and normal gastric mucosa tissues, respectively, we identified genes that were differentially expressed in gastric tumor endothelial (TEC) and normal endothelial cells (NEC) using DNA oligomer chips. Using reverse transcriptase-PCR, we confirmed the chip results by showing that Nrp2 gene expression is significantly up-regulated in TEC. Genes that were found to be up-regulated in TEC were also observed to be up-regulated in human umbilical vein endothelial cells (HUVECs) that were co-cultured with gastric cancer cells. In addition, HUVECs co-cultured with gastric cancer cells showed an increased reactivity to VEGF-induced proliferation and migration. Moreover, overexpression of Nrp2 in HUVECs significantly enhanced the proliferation and migration induced by VEGF. Observation of an immunohistochemical analysis of various human tumor tissue arrays revealed that Nrp2 is highly expressed in the tumor vessel lining and to a lesser extent in normal tissue microvessels. From these results, we suggest that Nrp2 may function to increase the response to VEGF, which is more significant in TEC than in NEC given the differential expression, leading to gastric TEC with aggressive angiogenesis phenotypes.
已知肿瘤脉管系统的结构和特征与正常血管不同。神经纤毛蛋白2（Nrp2）在非内皮细胞类型（如神经元或癌细胞）中表达，作为信号素和血管内皮生长因子（VEGF）的受体发挥作用。分别从晚期胃癌组织和正常胃黏膜组织中分离出肿瘤内皮细胞和正常内皮细胞后，我们使用DNA寡聚体芯片鉴定了在胃肿瘤内皮细胞（TEC）和正常内皮细胞（NEC）中差异表达的基因。通过逆转录聚合酶链反应，我们证实了芯片结果，表明Nrp2基因在TEC中表达显著上调。在与胃癌细胞共培养的人脐静脉内皮细胞（HUVEC）中也观察到在TEC中上调的基因。此外，与胃癌细胞共培养的HUVEC对VEGF诱导的增殖和迁移反应性增加。而且，Nrp2在HUVEC中的过表达显著增强了VEGF诱导的增殖和迁移。对各种人类肿瘤组织阵列的免疫组织化学分析观察显示，Nrp2在肿瘤血管内衬中高度表达，在正常组织微血管中表达程度较低。从这些结果来看，我们认为Nrp2可能起到增加对VEGF反应的作用，鉴于差异表达，这种作用在TEC中比在NEC中更显著，从而导致具有侵袭性血管生成表型的胃TEC。
