Angiostatin directly inhibits human prostate tumor cell invasion by blocking plasminogen binding to its cellular receptor, CD26.
Previous studies demonstrate that one of the six plasminogen type 2 glycoforms, plasminogen 2epsilon, enhances invasiveness of the 1-LN human prostate tumor cell line in an in vitro model. Binding of plasminogen 2epsilon to CD26 on the cell surface induces a Ca(2+) signaling cascade which stimulates the expression of matrix metalloproteinase-9, required by these cells to invade Matrigel. We now report that angiostatin, a fragment derived from plasminogen which prevents endothelial cell proliferation, is also a potent, direct inhibitor of 1-LN tumor cell invasiveness. We studied the effect of individual plasminogen 2 glycoform-derived angiostatins and found that only angiostatin 2epsilon binds to CD26 on the surface of 1-LN cells at a site also recognized by plasminogen 2epsilon. As a result, the plasminogen 2epsilon-induced Ca(2+) signaling cascade is inhibited, the expression of matrix metalloproteinase-9 is suppressed, and invasion of Matrigel by 1-LN cells is blocked. Angiostatin 2epsilon is also the only angiostatin glycoform which is able to inhibit in vitro endothelial cell proliferation and tubule formation. These studies suggest that, in addition to its ability to inhibit tumor vascularization, angiostatin 2epsilon may also directly block tumor metastasis.
Gonzalez-Gronow
Mario
M
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA. gonza002@mc.duke.edu
Grenett
Hernan E
HE
Gawdi
Govind
G
Pizzo
Salvatore V
SV
D043168:Angiostatins / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects*; D018819:Dipeptidyl Peptidase 4 / Q000276:immunology*; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D014407:Tumor Cells, Cultured
D043168:Angiostatins; D010958:Plasminogen; D018819:Dipeptidyl Peptidase 4; D020780:Matrix Metalloproteinase 9