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Angiostatin generation by human tumor cell lines: Involvement of plasminogen activators
Author(s) -
Westphal Johan R.,
Van't Hullenaar Rianne,
GeurtsMoespot Anneke,
Sweep Fred C.J.G.,
Verheijen Jan H.,
Bussemakers Marion M.G.,
Askaa Jon,
Clemmensen Inge,
Eggermont Alexander A.M.,
Ruiter Dirk J.,
De Waal Robert M.W.
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(20000615)86:6<760::aid-ijc2>3.0.co;2-4
Subject(s) - angiostatin , plasmin , cell culture , angiogenesis , cancer research , biology , microbiology and biotechnology , chemistry , pathology , medicine , biochemistry , enzyme , genetics
Angiostatin is a tumor‐derived angiogenesis inhibitor consisting of an internal fragment of plasminogen. Little is known about the production of angiostatin by human tumors. In this study, we examined the in vitro angiostatin‐generating capacities of a panel of human tumor cell lines (total n = 75) and the proteolytic molecule(s) involved. Angiostatin formation was determined by assessing the level of plasminogen digestion in conditioned medium by Western‐blot analysis. We found that the capacity to produce angiostatin is a common feature of many cell lines, depending on the tumor type. All 6 bladder‐carcinoma and 6 out of 7 prostate‐carcinoma cell lines showed intermediate to potent angiostatin‐generating activity. In contrast, only 2 out of 7 colon‐carcinoma and 2 out of 9 renal‐cell carcinoma cell lines were able to generate angiostatin at intermediate levels. Out of 25 melanoma cell lines, only one line failed to generate angiostatin. In the other cell‐line groups (cervix, breast and ovary), angiostatin formation varied. Remarkably, angiostatin bands were not of equal size in all plasminogen digests. Since reported data have indicated that plasminogen activators (uPA and tPA) were able to excise the angiostatin fragment from the plasminogen parent molecule via plasmin generation, we determined levels of uPA and tPA and PAI‐1 antigen in the conditioned media, and correlated the results with angiostatin‐generating capacity. Whereas prostate‐ and bladder‐carcinoma lines capable of generating high levels of angiostatin showed high uPA levels, angiostatin generation in melanoma cell lines was correlated with tPA levels. Generally, angiostatin non‐producers did not express uPA or tPA. In 6 out of 75 cell lines, however, we found angiostatin generation combined with low or absent levels of plasminogen activator, suggesting the involvement of alternative proteolytic pathways in the generation of angiostatin. Int. J. Cancer 86:760–767, 2000. © 2000 Wiley‐Liss, Inc.