EphB4 overexpression in B16 melanoma cells affects arterial-venous patterning in tumor angiogenesis.
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 EphB4 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 EphB4 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.
Huang
Xiaoyong
X
Department of Stem Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Yamada
Yoshihiro
Y
Kidoya
Hiroyasu
H
Naito
Hisamichi
H
Nagahama
Yumi
Y
Kong
Lingyu
L
Katoh
Shin-Ya
SY
Li
Weng-lin
WL
Ueno
Masaya
M
Takakura
Nobuyuki
N
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology; D017209:Apoptosis / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D036388:Ephrin-B2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D036224:Receptor, EphB4 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
D000911:Antibodies, Monoclonal; D036388:Ephrin-B2; C086681:Ephb4 protein, mouse; D036224:Receptor, EphB4