Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1.
Thrombospondin-1 (TSP-1) is a naturally occurring inhibitor of angiogenesis that limits vessel density in normal tissues and curtails tumor growth. Here, we show that the inhibition of angiogenesis in vitro and in vivo and the induction of apoptosis by thrombospondin-1 all required the sequential activation of CD36, p59fyn, caspase-3 like proteases and p38 mitogen-activated protein kinases. We also detected increased endothelial cell apoptosis in situ at the margins of tumors in mice treated with thrombospondin-1. These results indicate that thrombospondin-1, and possibly other broad-spectrum natural inhibitors of angiogenesis, act in vivo by inducing receptor-mediated apoptosis in activated microvascular endothelial cells.
Jiménez
B
B
Department of Microbiology, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, 60611, USA.
Volpert
O V
OV
Crawford
S E
SE
Febbraio
M
M
Silverstein
R L
RL
Bouck
N
N
D043168:Angiostatins; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D018955:CD36 Antigens / Q000235:genetics / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000473:pathology / Q000556:secondary; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000503:physiopathology* / Q000517:prevention & control; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D010958:Plasminogen / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn; D015398:Signal Transduction / Q000502:physiology; D019700:Thrombospondin 1 / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D018955:CD36 Antigens; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019700:Thrombospondin 1; D016222:Fibroblast Growth Factor 2; D043168:Angiostatins; D010958:Plasminogen; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases