Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors
Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors
复制标题
DOI：
10.1158/0008-5472.can-05-3387
复制
发表时间：
2006-02-15
期刊：
影响因子：
11.2
通讯作者：
Klagsbrun, M
中科院分区：
文献类型：
--
作者：
Amin, DN;Hida, K;Klagsbrun, M
表皮生长因子（EGF）受体家族成员由肿瘤细胞表达并促进肿瘤进展。表皮生长因子受体在内皮细胞中的表达和活性不太清楚。对肿瘤来源的内皮细胞的分析表明，它们表达EGFR、ErbB2和ErbB4，而它们的正常对应物表达ErbB2、ErbB3和ErbB4。在体内也观察到肿瘤血管中EGFR表达的增加和ErbB3表达的丧失。由于它们表达EGFR，肿瘤内皮细胞通过激活EGFR和ErbB2，通过激活下游丝裂原活化蛋白激酶途径和通过增强增殖来响应EGF和其他EGF家族成员。另一方面，正常内皮细胞对EGF没有反应，而是对ErbB3和ErbB4的配体神经调节蛋白（NRG）有反应。NRG激活正常内皮细胞中的ErbB3并抑制这些细胞的生长。相反，不表达ErbB3的肿瘤内皮细胞不受NRG的生长抑制。此外，由于它们表达EGFR，与正常内皮细胞不同，肿瘤内皮细胞是EGFR激酶抑制剂的直接靶标。这些低分子量化合物阻断EGF诱导的EGFR活化和肿瘤内皮细胞增殖。这些结果表明，获得EGF诱导的内皮细胞增殖，和NRG诱导的肿瘤内皮细胞生长抑制的损失构成了一个开关，促进肿瘤血管生成。此外，这些结果表明，EGFR激酶抑制剂可能是有效的抗血管生成治疗特异性靶向肿瘤，但不是正常的，血管。
Epidermal growth factor (EGF) receptor family members are expressed by tumor cells and contribute to tumor progression. The expression and activity of EGF receptors in endothelial cells are less well characterized. Analysis of tumor-derived endothelial cells showed that they express EGFR, ErbB2, and ErbB4, whereas their normal counterparts express ErbB2, ErbB3, and ErbB4. The gain in expression of EGFR and the loss of ErbB3 expression in tumor vasculature was also observed in vivo. As a consequence of their expressing EGFR, tumor endothelial cells responded to EGF and other EGF family members by activating both EGFR and ErbB2, by activating the downstream mitogen-activated protein kinase pathway, and by enhanced proliferation. On the other hand, normal endothelial cells did not respond to EGF but instead were responsive to neuregulin (NRG), a ligand for ErbB3 and ErbB4. NRG activated ErbB3 in normal endothelial cells and inhibited growth of these cells. In contrast, tumor endothelial cells, which do not express ErbB3, were not growth inhibited by NRG. Furthermore, due to their expression of EGFR, tumor endothelial cells, unlike normal endothelial cells, are direct targets for EGFR kinase inhibitors. These low-molecular-weight compounds block EGF-induced EGFR activation and proliferation of tumor endothelial cells. These results suggest that a gain of EGF-induced endothelial cell proliferation, and loss of NRG-induced growth inhibition in tumor endothelial cells constitutes a switch that promotes tumor angiogenesis. In addition, these results suggest that EGFR kinase inhibitors may be effective for antiangiogenesis therapy by specifically targeting the tumor, but not the normal, vasculature.