NF-kappaB activation in endothelial cells is critical for the activity of angiostatic agents.
In tumor cells, the transcription factor NF-kappaB has been described to be antiapoptotic and proproliferative and involved in the production of angiogenic factors such as vascular endothelial growth factor. From these data, a protumorigenic role of NF-kappaB has emerged. Here, we examined in endothelial cells whether NF-kappaB signaling pathway is involved in mediating the angiostatic properties of angiogenesis inhibitors. The current report describes that biochemically unrelated agents with direct angiostatic effect induced NF-kappaB activation in endothelial cells. Our data showed that endostatin, anginex, angiostatin, and the 16-kDa N-terminal fragment of human prolactin induced NF-kappaB activation in endothelial cells in both cultured human endothelial cells and in vivo in a mouse tumor model. It was also found that NF-kappaB activity was required for the angiostatic activity, because inhibition of NF-kappaB in endothelial cells impaired the ability of angiostatic agents to block sprouting of endothelial cells and to overcome endothelial cell anergy. Therefore, activation of NF-kappaB in endothelial cells can result in an unexpected antitumor outcome. Based on these data, the current approach of systemic treatment with NF-kappaB inhibitors may therefore be revisited because NF-kappaB activation specifically targeted to endothelial cells might represent an efficient strategy for the treatment of cancer.
Tabruyn
Sebastien P
SP
Angiogenesis Laboratory, Department of Pathology, Research, School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherland.
Mémet
Sylvie
S
Avé
Patrick
P
Verhaeghe
Catherine
C
Mayo
Kevin H
KH
Struman
Ingrid
I
Martial
Joseph A
JA
Griffioen
Arjan W
AW
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000098:blood supply; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020533:Angiogenesis Inhibitors; D017931:DNA Primers; D016328:NF-kappa B