EphB4 overexpression in B16 melanoma cells affects arterial-venous patterning in tumor angiogenesis
EphB4 overexpression in B16 melanoma cells affects arterial-venous patterning in tumor angiogenesis
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DOI：
10.1158/0008-5472.can-07-0531
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Takakura, Nobuyuki
中科院分区：
文献类型：
--
作者：
Huang, Xiaoyong;Yamada, Yoshihiro;Takakura, Nobuyuki
EphB4受体及其配体ephrinB2在胚胎发育过程中的血管发育中起重要作用。在血管中，ephrinB2在动脉内皮细胞（EC）和间充质支持细胞中表达，而FphB4仅在静脉EC中表达。以前，我们报道了OP9基质细胞，支持动脉和静脉EC的发展，其中EphB4过表达，可以抑制胚胎组织器官培养系统中ephrinB2阳性（ephrinB2（+））EC的发展。虽然EphB4受体在多种肿瘤细胞中表达，但其在调节肿瘤进展中的确切功能尚未明确显示。在此，我们发现EphB4在B16黑色素瘤细胞中的过表达抑制了皮下移植瘤中的肿瘤生长。移植瘤模型对这些肿瘤的组织学检查显示，B16细胞中FphB4过表达选择性抑制动脉ephrinB2（+）EC的发展。通过将表达ephrinB2的SV40转化的小鼠内皮细胞（SVEC）与EphB4过表达的B16细胞共培养，我们发现EphB4诱导SVEC凋亡。然而，ephrinB2并不诱导EphB4过表达的B16细胞凋亡。基于这些实验的结果，我们得出结论，EphB4在B16肿瘤细胞中的过表达通过经由ephrinB2的反向信号传导抑制肿瘤中动脉EC的存活。
EphB4 receptor and its ligand ephrinB2 play an important role in vascular development during embryogenesis. In blood vessels, ephrinB2 is expressed in arterial endothelial cells (EC) and mesenchymal supporting cells, whereas FphB4 is only expressed in venous ECs. Previously, we reported that OP9 stromal cells, which support the development of both arterial and venous ECs, in which EphB4 was overexpressed, could inhibit ephrinB2-positive (ephrinB2(+)) EC development in an embryonic tissue organ culture system. Although the EphB4 receptor is expressed in a variety of tumor cells, its exact function in regulating tumor progression has not been clearly shown. Here we found that overexpression of EphB4 in B16 melanoma cells suppressed tumor growth in a s.c. transplantation tumor model. Histologic examination of these tumors revealed that FphB4 overexpression in B16 cells selectively suppressed arterial ephrinB2(+) EC development. By coculturing ephrinB2-expressing SV40-transformed mouse ECs (SVEC) with EphB4-overexpressing B16 cells, we found that EphB4 induced the apoptosis of SVECs. However, ephrinB2 did not induce the apoptosis of EphB4-overexpressing B16 cells. Based on results from these experiments, we concluded that EphB4 overexpression in B16 tumor cells suppresses the survival of arterial ECs in tumors by a reverse signaling via ephrinB2.