Regulation of angiostatin production by matrix metalloproteinase-2 in a model of concomitant resistance.
We have previously reported the identification of the endogenous angiogenesis inhibitor angiostatin, a specific inhibitor of endothelial cell proliferation in vitro and angiogenesis in vivo. In our original studies, we demonstrated that a Lewis lung carcinoma (LLC-LM) primary tumor could suppress the growth of its metastases by generating angiostatin. Angiostatin, a 38-kDa internal fragment of plasminogen, was purified from the serum and urine of mice bearing LLC-LM, and its discovery provides the first proven mechanism for concomitant resistance (O'Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M. A., Lane, W. S., Cao, Y., Sage, E. H., and Folkman, J. (1994) Cell 79, 315-328). Subsequently, we have shown that systemic administration of angiostatin can regress a wide variety of malignant tumors in vivo. However, at the time of our initial discovery of angiostatin, the source of the protein was unclear. We hypothesized that the tumor or stromal cells might produce an enzyme that could cleave plasminogen sequestered by the primary tumor into angiostatin. Alternatively, we speculated that the tumor cells might express angiostatin. By Northern analysis, however, we have found no evidence that the tumor cells express angiostatin or other fragments of plasminogen (data not shown). We now report that gelatinase A (matrix metalloproteinase-2), produced directly by the LLC-LM cells, is responsible for the production of angiostatin, which suppresses the growth of metastases in our original model.
O'Reilly
M S
MS
Laboratory of Surgical Research, Department of Surgery, The Children's Hospital, Boston, Massachusetts 02115, USA.
Wiederschain
D
D
Stetler-Stevenson
W G
WG
Folkman
J
J
Moses
M A
MA
D043168:Angiostatins; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D017077:Culture Media, Conditioned; D004730:Endothelium, Vascular; D005780:Gelatin / Q000378:metabolism; D008175:Lung Neoplasms; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000494:pharmacology; D010958:Plasminogen / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017421:Sequence Analysis; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D010446:Peptide Fragments; D012333:RNA, Messenger; D043168:Angiostatins; D005780:Gelatin; D010958:Plasminogen; D020778:Matrix Metalloproteinase 2