Human prostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis inhibitor, angiostatin.
Angiostatin is an inhibitor of angiogenesis and metastatic growth that is found in tumor-bearing animals and can be generated in vitro by the proteolytic cleavage of plasminogen. The mechanism by which angiostatin is produced in vivo has not been defined. We now demonstrate that human prostate carcinoma cell lines (PC-3, DU-145, and LN-CaP) express enzymatic activity that can generate bioactive angiostatin from purified human plasminogen or plasmin. Affinity purified PC-3-derived angiostatin inhibited human endothelial cell proliferation, basic fibroblast growth factor-induced migration, endothelial cell tube formation, and basic fibroblast growth factor-induced corneal angiogenesis. Studies with proteinase inhibitors demonstrated that a serine proteinase is necessary for angiostatin generation. These data indicate that bioactive angiostatin can be generated directly by human prostate cancer cells and that serine proteinase activity is necessary for angiostatin generation.
Gately
S
S
Division of Hematology/Oncology, Northwestern University School of Medicine, Chicago, Illinois 60611, USA.
Twardowski
P
P
Stack
M S
MS
Patrick
M
M
Boggio
L
L
Cundiff
D L
DL
Schnaper
H W
HW
Madison
L
L
Volpert
O
O
Bouck
N
N
Enghild
J
J
Kwaan
H C
HC
Soff
G A
GA
D043168:Angiostatins; D006801:Humans; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000494:pharmacology; D010958:Plasminogen / Q000096:biosynthesis* / Q000378:metabolism* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000502:physiology*; D014407:Tumor Cells, Cultured
D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen; D012697:Serine Endopeptidases