Angiostatin directly inhibits human prostate tumor cell invasion by blocking plasminogen binding to its cellular receptor, CD26

• Published in: Experimental cell research Vol. 303; no. 1; pp. 22 - 31
• Main Authors: Gonzalez-Gronow, Mario, Grenett, Hernan E., Gawdi, Govind, Pizzo, Salvatore V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2005
• Subjects: 60 APPLIED LIFE SCIENCES; Angiogenesis; Angiostatin and prostate cancer; Angiostatin glycoforms; Angiostatins - pharmacology; CALCIUM IONS; CD26 and angiostatin binding; Cell Movement - drug effects; CELL PROLIFERATION; Dipeptidyl Peptidase 4 - immunology; Endothelial Cells - cytology; Endothelial Cells - metabolism; FIBRINOLYSIN; Humans; IN VITRO; Male; Matrix Metalloproteinase 9 - metabolism; METASTASES; NEOPLASMS; PLASMINOGEN; Plasminogen - metabolism; Plasminogen receptors; PROSTATE; Prostatic Neoplasms - metabolism; RECEPTORS; TUBULES; TUMOR CELLS; Tumor Cells, Cultured; Tumor invasion and angiostatin; VEINS; MMP; Angiogenesis; Angiostatin and prostate cancer; Plasminogen receptors; Pg; HUVEC; Angiostatin glycoforms; CD26; Tumor invasion and angiostatin; u-PA; Pm; CD26 and angiostatin binding
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2004.09.008

Previous studies demonstrate that one of the six plasminogen type 2 glycoforms, plasminogen 2ɛ,  enhances invasiveness of the 1-LN human prostate tumor cell line in an in vitro model. Binding of plasminogen 2ɛ  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 2ɛ binds to CD26 on the surface of 1-LN cells at a site also recognized by plasminogen 2ɛ. As a result, the plasminogen 2ɛ-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 2ɛ 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 2ɛ may also directly block tumor metastasis.