PubMed · 9715627
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
A Gawande. 1998. Mouse hunt.. https://pubmed.ncbi.nlm.nih.gov/9715627/
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
Angiostatin, a product of the proteolytic cleavage of plasminogen, possesses potent antitumor and antiangiogenic properties in vivo. Studies with cultured endothelial cells suggest that under certain conditions, angiostatin inhibits the migration and proliferation of these cells or, alternatively, increases their rate of apoptosis. In general, the effects of angiostatin have been considerably less potent in vitro than in vivo. One potential explanation for this disparity is that the in vivo target of angiostatin is not the mature endothelial cell. Recently, evidence has accumulated to show that circulating endothelial progenitor cells (EPCs) contribute to neovascularization. In this study, we have isolated EPCs from human subjects and demonstrated that, in contrast to that of mature endothelial cells, the growth of EPCs is exquisitely sensitive to angiostatin. These results suggest that angiostatin and related compounds may exert their biological effects by inhibiting the contribution of EPCs to angiogenesis and not by altering the growth of mature endothelial cells.
Although the therapeutic value of angiostatin, a proteolytic fragment of plasminogen, has been recognized for the treatment of cancer, the production of bioactive angiostatin remains a difficult task. Here we report that expression of a cDNA encoding a secreted, four-kringle human angiostatin inhibited tumor growth of B16F10 melanoma cells in mice but did not suppress tumor cell growth in culture. After transfection and selection, stable expression of the angiostatin cDNA was demonstrated in several B16F10 clones by quantitative mRNA analysis using the Taqman method. Cells that expressed angiostatin at either a low, medium, or high level were injected into C57BL/6 mice. s.c. Growth of B16F10 tumors was diminished by the angiostatin transgene, and the inhibition was directly proportional to the expression level of angiostatin in the transfected cells. However, suppression of s.c. tumor growth was transient, and eventually, tumors emerged with a strongly decreased expression of the transgene. Angiostatin expression also reduced lung metastasis from i.v.-injected B16F10 cells. Our data indicate that a cDNA encoding bioactive human angiostatin is potentially useful for gene therapy of human cancers, but the delivery of the transgene may require repeated dosing to achieve sustained dormancy of primary tumors and cancer metastases.
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.