Conclusions
In the present overview, the multifunctional capacity of the uPA-system in tumor biological processes was emphasized. In addition to its central role in pericellular proteolysis, uPA/uPAR-mediated activities contribute to many different processes like cell proliferation, adhesion, migration, and angiogenesis. Whereas extracellular PAI-2 solely acts as an inhibitor of uPA (and tPA), PAI-1 clearly exerts additional functions, e. g. involvement in modulation of uPAR- and integrin-mediated cell adhesion as well as in redistribution of uPAR on the tumor cell surface supporting the reorganization of the invasive front. Selective synthetic active site inhibitors of uPA may serve as novel therapeutic agents for anti-invasive and anti-proliferative cancer therapy.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Alonso, D.F., Farias, E.F., Ladeda, V., Davel, L., Puricelli, L., and Bal, d. K.J., 1996, Effects of synthetic urokinase inhibitors on local invasion and metastasis in a murine mammary tumor model. Breast Cancer Res. Treat 40: 209–223.
Alonso, D.F., Tejera, A.M., Farias, E.F., Bal, d. K.J., and Gómez, D E., 1998, Inhibition of mammary tumor cell adhesion, migration, and invasion by the selective synthetic urokinase inhibitor B428. Anticancer Res. 18: 4499–4504.
Andreasen, P.A., Kjøller, L., Christensen, L., and Duffy, M.J., 1997, The urokinase-type plasminogen activator system in cancer metastasis: a review. Int. J. Cancer 72: 1–22.
Åstedt, B., Lindoff, C., and Lecander, I., 1998, Significanceof the plasminogen activator inhibitor of placental type (PAI-2) in pregnancy. Semin. Thromb. Hemost. 24: 431–435.
Bajou, K., Noël, A., Gerard, R.D., Masson, V., Brünner, N., Holst-Hansen, C., Skobe, M., Fusenig, N.E., Carmeliet, P., Collen, D., and Foidart, J.M., 1998, Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat. Med.. 4: 923–928.
Berkenpas, M. B., Lawrence, D. A., and Ginsburg, D., 1995, Molecular evolution of plasminogen activator inhibitor-1 functional stability. EMBOJ. 14: 2969–2977.
Billström, A., Hartley-Asp, B., Lecander, I., Batra, S., and Åstedt, B., 1995, The urokinase inhibitor p-aminobenzamidine inhibits growth of a human prostate tumor in SCID mice. Int. J. Cancer 61: 542–547.
Blasi, F., 1997, uPA, uPAR, PAI-1: key intersection of proteolytic, adhesive and chemotactic highways? Immunol. Today 18: 415–417.
Carmeliet, P., Kieckens, L., Schoonjans, L., Ream, B., van Nuffelen, A., Prendergast, G., Cole, M., Bronson, R., Collen, D., and Mulligan, R.C., 1993a, Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization. J. Clin. Invest. 92: 2746–2755.
Carmeliet, P., Stassen, J.M., Schoonjans, L., Ream, B., van den Oord, J J., De Mol, M., Mulligan, R.C., and Collen, D., 1993b, Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J. Clin. Invest. 92: 2756–2760.
Casslén, B., Gustavsson, B., Angelin, B., and Gåfvels, M., 1998, Degradation of urokinase plasminogen activator (uPA) in endometrial stromal cells requires both the uPA receptor and the low-density lipoprotein receptor-related protein/alpha2-macroglobulin receptor. Mol. Hum. Reprod. 4: 585–593.
Conese, M., and Blasi, F., 1995, Urokinase/urokinase receptor system: internalization/degradation of urokinase-serpin complexes: mechanism and regulation. Biol. Chem. Hoppe Seyler 376: 143–155.
Dougherty, K.M., Pearson, J.M., Yang, A.Y., Westrick, R..J., Baker, M.S., and Ginsburg, D., 1999, The plasminogen activator inhibitor-2gene is not required for normal murine development or survival. Proc. Natl. Acad. Sci. USA 96: 686–691.
Egelund, R., Schousboe, S.L., Sottrup-Jensen, L., Rodenburg, K.W., and Andreasen, P.A., 1997, Type-1 plasminogen-activator inhibitor-conformational differences betweenlatent, active, reactive-centre-cleaved and plasminogen-activator-complexed forms, as probed by proteolytic susceptibility. Eur. J. Biochem. 248: 775–785.
Eitzman, D.T., and Ginsburg, D., 1997, Of mice and men. The function of plasminogen activator inhibitors (PAIs) in vivo. Adv. Exp. Med. Biol 425: 131–141.
Félez J., 1998, Plasminogen binding to cell surfaces. Fibrinol. Proteol 12: 183–189.
Foekens, J.A., Buessecker, F., Peters, H.A., Krainick, U., van Putten, W.L., Look, M.P., Klijn, J.G., and Kramer, M.D., 1995, Plasminogen activator inhibitor-2: prognostic relevance in 1012 patients with primary breast cancer. Cancer Res. 55: 1423–1427.
Goretzki, L., Schmitt, M., Mann, K., Calvete, J., Chucholowski, N., Kramer, M., Günzler, W. A., Jänicke, F., and Graeff, H., 1992, Effective activation of the proenzyme form of the urokinase-typeplasminogen activator (pro-uPA) by the cysteine protease cathepsin L. FEBS Lett. 297: 112–118.
Hahn-Dantona, E., Ramos-DeSimone, N., Sipley, J., Nagase, H., French, D.L., and Quigley, J.P., 1999, Activation of proMMP-9 by a plasmin/MMP-3 cascade in a tumor cell model. Regulation by tissue inhibitors of metalloproteinases. Ann. NY Acad. Sci. 878: 372–387.
Harrop, S.J., Jankova, L., Coles, M., Jardine, D., Whittaker, J.S., Gould, A.R., Meister, A., King, G.C., Mabbutt, B.C., and Curmi, P.M., 1999, The crystal structure of plasminogen activator inhibitor 2 at 2.0 Å resolution: implications for serpin function. Structure Fold Des. 7: 43–54.
Hauptmann, J., and Stürzebecher, J., 1999, Synthetic inhibitors of thrombin and factor Xa: from bench to bedside. Thromb. Res. 93: 203–241.
Jankun, J., Keck, R W., Skrzypczak-Jankun, E., and Swiercz, R., 1997, Inhibitors of urokinase reduce size of prostate cancer xenografts in severe combined immunodeficient mice. Cancer Res. 57: 559–563.
Kanse, S.M., Kost, C., Wilhelm, O.G., Andreasen, P.A., and Preissner, K.T., 1996, The urokinase receptor is a major vitronectin-binding protein on endothelialcells. Exp. Cell. Res. 224: 344–353.
Kjøller, L., Kanse, S.M., Kirkegaard, T., Rodenburg, K.W., Ronne, E., Goodman, S.L., Preissner, K.T., Ossowski, L., and Andreasen, P.A., 1997, Plasminogen activator inhibitor-1 represses integrin-and vitronectin-mediated cell migration independently of its function as aninhibitor of plasminogen activation. Exp.Cell Res. 232: 420–429.
Kobayashi, H., Schmitt, M., Goretzki, L., Chucholowski, N., Calvete, J., Kramer, M., Günzler, W.A., Jänicke, F., and Graeff, H., 1991, Cathepsin B efficiently activates the soluble and the tumor cell receptor-bound form of the proenzyme urokinase-type plasminogen activator (pro-uPA). J. Biol. Chem. 266: 5147–5152.
Look, M.P. and Foekens, J.A., 1999, Clinicalrelevance of the urokinase plasminogen activator system in breast cancer. APMIS 107: 150–159.
Loskutoff, D.J., Curriden, S.A., Hu, G., and Deng, G., 1999, Regulation of cell adhesion by PAI-1. APMIS 107: 54–61.
Murphy, G., Knäuper, V., Cowell, S., Hembry, R., Stanton, H., Butler, G., Freije, J., Pendás, A.M., and López-Otin, C., 1999, Evaluation of some newer matrix metalloproteinases. Ann. NY Acad. Sci. 878: 25–39.
Ny, T., and Mikus, P., 1997 Plasminogen activatorinhibitor type-2. A spontaneously polymerizing serpin that exists in two topological forms. Adv. Exp. Med. Biol. 425: 123–130.
Nykjaer, A., Conese, M., Christensen, E.I., Olson, D., Cremona, O., Gliemann, J., and Blasi, F., 1997, Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes. EMBO J. 16: 2610–2620.
Rabbani, S. A., Harakidas, P., Davidson, D J., Henkin, J., and Mazar, A.P., 1995, Prevention of prostate-cancer metastasis in vivo by a novel synthetic inhibitor of urokinase-type plasminogen activator (uPA). Int. J. Cancer 63: 840–845.
Ragno, P., Montuori, N., and Rossi, G., 1995, Urokinase-type plasminogen activator/type-2 plasminogen-activatorinhibitor complexes are not internalized upon binding to the urokinase-type-plasminogen-activator receptor in THP-1 cells. Interaction of urokinase-type plasminogen activator/type-2 plasminogen-activator inhibitor complexes with the cell surface. Eur. J. Biochem. 233: 514–519.
Ragno, P., Montuori, N., Vassalli, J.D., and Rossi, G., 1993, Processing of complex between urokinase and its type-2 inhibitor on the cell surface. A possible regulatory mechanism of urokinase activity. FEBS Lett. 323: 279–284.
Reuning, U., Magdolen, V., Wilhelm, O.G., Fischer, K., Lutz, V., Graeff, H., and Schmitt, M., 1998, Multifunctional potential of the plasminogen activation system in tumor invasion and metastasis. Int. J. Oncol. 13: 893–906.
Schmitt, M., Harbeck, N., Thomssen, C., Wilhelm, O.G., Magdolen, V., Reuning, U., Ulm, K., Hföler, H., Jänicke, F., and Graeff, H., 1997, Clinical impact of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target for therapy. Thromb. Haemost 78: 285–296.
Sharp, A.M., Stein, P.E., Pannu, N.S., Carrell, R.W., Berkenpas, M.B., Ginsburg, D., Lawrence, D.A., and Read, R.J., 1999, The active conformation of plasminogen activator inhibitor 1, a target for drugs to control fibrinolysis and cell adhesion. Structure 7: 111–118.
Sprengers, E.D., and Kluft, C., 1987, Plasminogen activator inhibitors. Blood 69: 381–387.
Stürzebecher, J. and Markwardt, F., 1978, Synthetic inhibitors of serine proteinases. 17. The effect of benzamidine derivatives on the activity of urokinase and the reduction of fibrinolysis. Pharmazie 33: 599–602.
Swiercz, R., Skrzypczak-Jankun, E., Merrell, M.M., Selman, S.H., and Jankun, J., 1999, Angiostatic activity of synthetic inhibitors of urokinase type plasminogen activator. Oncol. Rep. 6: 523–526.
Tidwell, R.R., Geratz, J.D., and Dubovi, E.J., 1983, Aromatic amidines: comparison of their ability to blockrespiratorysyncytial virus induced cell fusion and to inhibit plasmin, urokinase, thrombin, and trypsin. J. Med. Chem. 26: 294–298.
Towle, M J., Lee, A., Maduakor, E.C., Schwartz, C.E., Bridges, A.J., and Littlefield, B.A., 1993, Inhibition of urokinase by 4-substituted benzo[b]thiophene-2-carboxamidines: an important new class of selective synthetic urokinase inhibitor. Cancer Res. 53: 2553–2559.
Vassalli, J.D. and Belin, D., 1987, Amiloride selectively inhibits the urokinase-type plasmino-gen activator. FEBS Lett. 214: 187–191.
Xing, R.H., Mazar, A., Henkin, J., and Rabbani, S.A., 1997, Prevention of breast cancer growth, invasion, and metastasis by antiestrogen tamoxifen alone or in combination with urokinase inhibitor B-428. Cancer Res. 57: 3585–3593.
Yang, H., Henkin, J., Kim, K.H., and Greer, J., 1990, Selective inhibition of urokinase by substituted phenylguanidines: quantitative structure-activity relationship analyses. J. Med. Chem. 33: 2956–2961.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Kluwer Academic Publishers
About this chapter
Cite this chapter
Magdolen, V. et al. (2002). Natural and Synthetic Inhibitors of The Tumor-Associated Serine Protease Urokinase-Type Plasminogen Activator. In: Langner, J., Ansorge, S. (eds) Cellular Peptidases in Immune Functions and Diseases 2. Advances in Experimental Medicine and Biology, vol 477. Springer, Boston, MA. https://doi.org/10.1007/0-306-46826-3_36
Download citation
DOI: https://doi.org/10.1007/0-306-46826-3_36
Publisher Name: Springer, Boston, MA
Print ISBN: 978-0-306-46383-9
Online ISBN: 978-0-306-46826-1
eBook Packages: Springer Book Archive