Abstract
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.
Highlights
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 vitro studies of cancer cell lines (3–7) have shown that a variety of enzymes can cleave plasminogen into fragments of plasminogen with a similar sequence and activity to that of the angiostatin protein we first described (1). None of these reports have identified the specific enzyme involved in the production of the biologically active angiostatin in the in vivo Lewis lung model in which angiostatin was first discovered nor have they demonstrated the production of angiostatin with identical sequence, composition, or biological activity to that which we first described
We have previously found that the in vivo phenotype of these cells can be changed after in vitro passage. To confirm that these cells would still form tumors that could suppress their metastases in vivo, they were injected into mice (1, 2)
Summary
Vol 274, No 41, Issue of October 8, pp. 29568 –29571, 1999 Printed in U.S.A. Regulation of Angiostatin Production by Matrix Metalloproteinase-2 in a Model of Concomitant Resistance*. In vitro studies of cancer cell lines (3–7) have shown that a variety of enzymes can cleave plasminogen into fragments of plasminogen with a similar sequence and activity to that of the angiostatin protein we first described (1). None of these reports have identified the specific enzyme involved in the production of the biologically active angiostatin in the in vivo Lewis lung model in which angiostatin was first discovered nor have they demonstrated the production of angiostatin with identical sequence, composition, or biological activity to that which we first described.
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