Role of ephrinB2 in nonproductive angiogenesis induced by Delta-like 4 blockade.
Delta-like 4 (DLL4) is one of the Notch ligands and plays an important role in vascular development. DLL4 blockade inhibits tumor growth by promoting nonproductive angiogenesis, which is characterized by an increase in vascular density and decrease in tissue perfusion. However, a detailed mechanism remains unclear. In this study, newly developed neutralizing antibodies against mouse and human DLL4 were used to investigate the possible involvement of VEGF-DLL4-ephrinB2 cascade in nonproductive angiogenesis caused by DLL4 blockade. DLL4 blockade and soluble ephrinB2 treatment suppressed tumor growth and induced nonproductive angiogenesis. DLL4 was expressed in subcutaneous tumors, and DLL4 blockade suppressed ephrinB2 expression in the tumors. DLL4 blockade significantly promoted human umbilical vein endothelial cell (HUVEC) proliferation in vitro, and the effect was additive to that of VEGF. Both DLL4 blockade and VEGF significantly increased cord length and branch points in a tubular formation assay. Expression of ephrinB2 in HUVECs was enhanced by VEGF alone, and the enhancement was inhibited by DLL4 blockade. Moreover, when we studied the effect of ephrinB2 RNA interference on HUVEC tubular formation, knockdown of ephrinB2 mimicked the effect of DLL4. These results suggest that ephrinB2 plays a crucial role in nonproductive angiogenesis caused by DLL4 blockade.
Yamanda
Shinsuke
S
Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ku, Sendai, Japan.
Ebihara
Satoru
S
Asada
Masanori
M
Okazaki
Tatsuma
T
Niu
Kaijun
K
Ebihara
Takae
T
Koyanagi
Akemi
A
Yamaguchi
Noriko
N
Yagita
Hideo
H
Arai
Hiroyuki
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D002135:Calcium-Binding Proteins; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D002455:Cell Division; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D036388:Ephrin-B2 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D036388:Ephrin-B2; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse