Advertisement

Angiostatin Protein and Other Plasminogen Fragments

  • B. Kim Lee Sim
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

In some experimental and clinical presentations ofetastatic disease, a primary tumor can inhibit the growth of its metastases. This phenomenon of the inhibition of tumor growth by tumor mass had been hypothesized to be caused by concomitant immunity (a resistance to second tumor graft in the presence of the first growing tumor) in early publications (1,2). Several other hypotheses have been proposed (reviewed in refs. 3 and 4) but, similarly, had not explained the mechanism of this phenomenon. O’Reilly and Folkman more recently proposed that the phenomenon is the result of the specific inhibition of metastatic growth by the primary tumor. They proposed that a primary tumor initiates its own neovascularization by generating angiogenesis stimulator(s) in excess of angiogenesis inhibitor(s). The positive regulators act most effectively around the primary tumor site, stimulating angiogenesis and primary tumor growth. By virtue of its longer half-life in circulation, negative regulators circulate to other distal sites and inhibit endothelial cell growth, which in turn causes inhibition of metastatic growth (5,6). The hypothesis proposed by O’Reilly and Folkman was validated with the identification of AngiostatinTM protein (AP) generated by the primary tumor, which inhibits angiogenesis and growth in a secondary metastasis (6). Data accumulated to date on the novel protein Angiostatin and another potent endogenous antiangiogenesis inhibitor, EndostatinTM protein, show that, indeed, tumor growth is dependent on angiogenesis (first proposed by Folkman [7]) and show that the inhibition of angiogenesis can in fact block the growth of metastases, as well as maintain tumors in a dormant state (6,8,9).

Keywords

Endothelial Cell Growth Lewis Lung Carcinoma Primary Tumor Growth Endothelial Cell Surface Metastatic Growth 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Ehrlich, P. and Apolant, H. (1905) Beobachtungen uber maligne Maustumoren. Berl. Klin. Wschr. 42, 871–874.Google Scholar
  2. 2.
    Bashford, E. F., Murray, J. A., and Cramer, W. (1907) Natural and induced resistance of mice to the growth of cancer. Proc. R. Soc. Lond. 79, 164–187.CrossRefGoogle Scholar
  3. 3.
    Gorelik, E. (1983) Resistance of tumor-bearing mice to a second tumor challenge. Cancer Res. 43,138–145.PubMedGoogle Scholar
  4. 4.
    Prehn, R. T. (1991) Inhibition of tumor growth by tumor mass. Cancer Res. 51, 2–4.PubMedGoogle Scholar
  5. 5.
    O’Reilly, M. S., Rosenthal, R., Sage, E. H., Smith, S., Holmgren, L., Moses, M., Shing, Y., and Folkman, J. (1993) Suppression of tumor metastases by a primary tumor. Surg. Forum 44, 474–476.Google Scholar
  6. 6.
    O’Reilly, M. S., Holmgren, L., Shing, Y., Chen, C., Rosenthal, R. A., Moses, M., et al. (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the supression of metastases by a Lewis lung carcinoma. Cell 79 315–328.Google Scholar
  7. 7.
    Folkman, J. (1971) Tumor angiogenesis: theraapeutic implications. N. Engl. J. Med. 285 1182–1186.Google Scholar
  8. 8.
    O’Reilly, M. S., Holmgren, L., Chen, C., and Folkman, J. (1996) Angiostatin induces and sustains dormancy of human primary tumors in mice. Nature Med. 2, 689–692.PubMedCrossRefGoogle Scholar
  9. 9.
    O’Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., et al. (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285.PubMedCrossRefGoogle Scholar
  10. 10.
    Saksela, O. (1985) Plasminogen activation and regulation ofpericellularproteolysis. Biochim. Biophys. Acta 823, 35–65.PubMedGoogle Scholar
  11. 11.
    Ponting, C. P., Marshall, J. M., and Cederholm-Williams, S. A. (1992) Plasminogen: a structural review. Blood Coagulation Fibrinolysis 3, 605–614.PubMedCrossRefGoogle Scholar
  12. 12.
    O’Reilly, M. S. (1997) Angiostatin: an endogenous inhibitor of angiogene of tumor growth. Exs. 79, 273–294.PubMedGoogle Scholar
  13. 13.
    Gonzalex-Gronow, M., Grenett, H. E., Fuller, G. M., and Pizzo, S. V. (1990) The role of carbohydrate in the function of human plasminogen: comparison of the protein obtained from molecular cloning and expression in Escherichia coli and COS cells. Biochm. Biophys. Acta. 1039, 269–276.CrossRefGoogle Scholar
  14. 14.
    Pirie-Shepherd, S. R., Stevens, R. D., Andon, N. L., Enghild, J. J., and Pizzo, S. V. (1997) Evidence for a novel 0-linked sialylated trisaccharide on Ser-248 of human plasminogen 2. J. Biol. Chem. 272, 7408–7411.PubMedCrossRefGoogle Scholar
  15. 15.
    Sim, B. K. L., O’Reilly, M. S., Liang, H., Fortier, A. H., He, W., Madsen, J. M., Lapcevich, R., and Nacy, C. A. (1997) Recombinant human Angiostatin protein inhibits experimental primary and metastatic cancer. Cancer Res. 57, 1329–1334.PubMedGoogle Scholar
  16. 16.
    Wu, Z., O’Reilly, M. S., Folkman, J., and Shing, Y. (1997) Suppression of tumor growth with recombinant murine Angiostatin. Biochem. Biophys. Res. Commun. 236, 651–654.PubMedCrossRefGoogle Scholar
  17. 17.
    Gately, S., Twardowski, P., Stack, S. M., Cundiff, D. L., Grella, D., Castellino, F. J., et al. (1997) Mechanism of cancer-mediated conversion of plasminogen to the angiogenesis inhibitor angiostatin. Proc. Natl. Acad. Sci. USA in press.Google Scholar
  18. 18.
    Holmgren, L., O’Reilly, M. S., and Folkman, J. (1995) Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med. 1, 149–153.PubMedCrossRefGoogle Scholar
  19. 19.
    Gately, S., Twardowski, P., Stack, S. M., Patrick, M., Boggio, L., Cundiff, D. L., et al. (1996) Human prostate carcinoma cells express enzymatic activity that converts human plasminogen to the angiogenesis inhibitor, Angiostatin. Cancer Res. 56, 4887–4890.PubMedGoogle Scholar
  20. 20.
    Dong, Z., Kumar, R., Yang, X., and Fidler, I. J. (1997) Macrophage-derived metalloelastase is responsible for the generation of Angiostatin in Lewis lung carcinoma. Cell 88, 801–810.PubMedCrossRefGoogle Scholar
  21. 21.
    Stathakis, P., Fitzgerald, M., Matthias, L. J., Chesterman, C. N., and Hogg, P. J. (1997) Generation of Angiostatin by reduction and proteolysis of plasmin. J. Biol. Chem. 272, 20,641–20,645.Google Scholar
  22. 22.
    Miles, L. A., Dahlberg, C. M., Plescia, J., Felez, J., Kato, K., and Plow, E. F. (1991) Role of cell-surface lysines in plasminogen binding to cells: identification of alpha-enolase as a candidate plasminogen receptor. Biochemistry 30, 1682–1691.PubMedCrossRefGoogle Scholar
  23. 23.
    Plow, E. F., Freaney, D. E., Plescia, J., and Miles, L. A. (1986) The plasminogen system and cell surfaces: evidence for plasminogen and urokinase receptors on the same cell type. J. Cell Biol. 103, 2411–2420.PubMedCrossRefGoogle Scholar
  24. 24.
    Miles, L. A. and Plow, E. F. (1985) Binding and activation ofplasminogen on the platelet surface. J. Biol. Chem. 260, 4303–4311.PubMedGoogle Scholar
  25. 25.
    Hajjar, K. A., Jacovina, A. T., and Chacko, J. (1994) Endothelial cell receptor for plasminogen/tissue plasminogen activator. I. Identity with annexin II. J. Biol. Chem. 33, 21,191–21,197.Google Scholar
  26. 26.
    Cesarman, G. M., Guevara, C. A., and Hajjar, K. A. (1994) An endothelial cell receptor forplasminogen/ tissue plasminogen activator (t-PA). J. Biol. Chem. 269, 21,198–21,203.Google Scholar
  27. 27.
    Castellino, F. J., Ploplis, V. A., Powell, J. R., and Strickland, D. K. (1981) Existence of independent domain structures in human Lys77-plasminogen. J. Biol. Chem. 256, 4778–4782.PubMedGoogle Scholar
  28. 28.
    Hoylaerts, M., Rijken, D. C., Lijnen, H. R., and Collen, D. (1982) Kinetics of the activation of plasminogen by human tissue plasminogen activator. J. Biol. Chem. 257, 2912–2919.PubMedGoogle Scholar
  29. 29.
    Markus, G., Evers, J. L., and Hobika, G. H. (1978) Comparison of some properties of native (Glu) and modified (Lys) human plasminogen. J. Biol. Chem. 253, 733–739.PubMedGoogle Scholar
  30. 30.
    Markus, G., Priore, R. L., and Wissler, F. C. (1979) Binding of tranexamic acid to native (Glu) and modified (Lys) human plasminogen and its effect on conformation. J. Biol. Chem. 254, 1211–1216.PubMedGoogle Scholar
  31. 31.
    Cao, Y., Ji, R. W., Davidson, D., Schaller, J. Marti, D., Sohndel, S., et al. (1996) Kringle domains of human angiostatin: characterization of the anti-proliferation activity on endothelial cells. J. Biol. Chem. 271, 29,461–29,467.Google Scholar
  32. 32.
    Cao, Y., Chen, A., An, S. S. A., Ji, R. W., Davidson, D., Cao, Y., and Llinas, M. (1997) Kringle 5 of plasminogen is a novel inhibitor of endothelial cell growth. 272, 22,924–22,928.Google Scholar
  33. 33.
    Melzig, M. F. and Loose, R. (1995) Investigations into the mechanism of toxicity of lipopolysaccharide (LPS) in bovine aortic endothelial cells. Pharmazie 50, 558–560.PubMedGoogle Scholar
  34. 34.
    Bannerman, D. D. and Goldblum, S. E. (1997) Endotoxin induces endothelial barrier dysfunction through protein tyrosine phosphorylation. Am. J. Physiol. 273, L217–226.Google Scholar
  35. 35.
    Shih, G. C. and Hajjar, K. A. (1993) Plasminogen and plasminogen activator assembly and the human endothelial cell. Proc. Soc. Exp. Biol. Med. 202, 258–264.PubMedGoogle Scholar
  36. 36.
    Keyt, B., Berleau, L., Nguyen, H., Heinshon, H., Chen, H., Vandlen, R., and Ferrara, N. (1996) Carboxyterminal domain (111–165) of VEGF is critical for mitogenic potency. J. Biol. Chem. 271, 7788–7795.PubMedCrossRefGoogle Scholar
  37. 37.
    Ferrara, N., and Davis-Smyth, T. (1997) Biology of vascular endothelial growth factor. Endocr. Rev. 18, 4–25.PubMedCrossRefGoogle Scholar
  38. 38.
    Kothakota, S., Azuma, T., Reinhard, C., Klippel, A., Tang, J., Chu, K., et al. (1997) Caspase-3-generated fragment of gelsolin: effector ofmorphological change in apoptosis. Science 278, 294–298.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • B. Kim Lee Sim

There are no affiliations available

Personalised recommendations