Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth.
We isolated and identified an endogenous 24-kDa human basement membrane-derived inhibitor of angiogenesis and tumor growth, termed canstatin. Canstatin, a fragment of the alpha2 chain of type IV collagen, was produced as a recombinant molecule in Escherichia coli and 293 embryonic kidneys cells. Canstatin significantly inhibited human endothelial cell migration and murine endothelial cell tube formation. Additionally, canstatin potently inhibited 10% fetal bovine serum-stimulated endothelial cell proliferation and induced apoptosis, with no inhibition of proliferation or apoptosis observed on non-endothelial cells. Inhibition of endothelial proliferation was not concomitant with a change in extracellular signal-regulated kinase activation. We demonstrate that apoptosis induced by canstatin was associated with a down-regulation of the anti-apoptotic protein, FLIP. Canstatin also suppressed in vivo growth of large and small size tumors in two human xenograft mouse models with histology revealing decreased CD31-positive vasculature. Collectively, these results suggest that canstatin is a powerful therapeutic molecule for suppressing angiogenesis.
Kamphaus
G D
GD
Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Masssachusetts 02215, USA.
Colorado
P C
PC
Panka
D J
DJ
Hopfer
H
H
Ramchandran
R
R
Torre
A
A
Maeshima
Y
Y
Mier
J W
JW
Sukhatme
V P
VP
Kalluri
R
R
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003001:Cloning, Molecular / Q000379:methods; D003094:Collagen / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D004926:Escherichia coli; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011651:Pulmonary Artery; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection
D020533:Angiogenesis Inhibitors; D011994:Recombinant Proteins; D003094:Collagen