Amyloid endostatin induces endothelial cell detachment by stimulation of the plasminogen activation system.
Endostatin is a fragment of collagen XVIII that acts as an inhibitor of tumor angiogenesis and tumor growth. Anti-tumor effects have been described using both soluble and insoluble recombinant endostatin. However, differences in endostatin structure are likely to cause differences in bioactivity. In the present study, we have investigated the cellular effects of insoluble endostatin. We previously found that insoluble endostatin shows all the hallmarks of amyloid aggregates and potently stimulates tissue plasminogen activator-mediated formation of the serine protease plasmin. We here show that amyloid endostatin induces plasminogen activation by endothelial cells, resulting in vitronectin degradation and plasmin-dependent endothelial cell detachment. Endostatin-mediated stimulation of plasminogen activation, vitronectin degradation, and endothelial cell detachment is inhibited by carboxypeptidase B, indicating an essential role for carboxyl-terminal lysines. Our results suggest that amyloid endostatin may inhibit angiogenesis and tumor growth by stimulating the fibrinolytic system.
Reijerkerk
Arie
A
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Mosnier
Laurent O
LO
Kranenburg
Onno
O
Bouma
Bonno N
BN
Carmeliet
Peter
P
Drixler
Tom
T
Meijers
Joost C M
JC
Voest
Emile E
EE
Gebbink
Martijn F B G
MF
D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D043424:Carboxypeptidase B / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy; D043169:Endostatins / Q000378:metabolism / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010958:Plasminogen / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D010958:Plasminogen; D043424:Carboxypeptidase B; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin