Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization

Abstract

Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase, but paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI1), have been correlated with a poor prognosis for some cancers. We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes. When this PAI1 deficiency was circumvented by intravenous injection of a replication-defective adenoviral vector expressing human PAI1, invasion and associated angio-genesis were restored. This experimental evidence demonstrates that host-produced PAI is essential for cancer cell invasion and angiogenesis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Blasi, F. Urokinase and urokinase receptor: a paracrine/autocrine system regulating cell migration and invasiveness. Bioessays 15, 105–111 (1993).

    Article  CAS  Google Scholar 

  2. Mignatti, P. & Rifkin, D.B. Biology and biochemistry of proteinases in tumor invasion. Physiol. Rev. 73, 161–195 (1993).

    Article  CAS  Google Scholar 

  3. Murphy, G., Atkinson, S., Ward, R., Gavrilovic, J. & Reynolds, J.J. The role of plasminogen activators in the regulation of connective tissue metalloproteinases. Ann. NY Acad. Sci. 667, 1–12 (1992).

    Article  CAS  Google Scholar 

  4. Andreasen, P.A., Kjoller, L., Christensen, L. & Duffy, M.J. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int. J. Cancer 72, 1–22 (1997).

    Article  CAS  Google Scholar 

  5. Ossowski, L., Russo-Payne, H. & Wilson E.L. Inhibition of urokinase-type plasminogen activator by antibodies: the effect on dissemination of a human tumor in the nude mouse. Cancer Res. 51, 274–281 (1991).

    CAS  PubMed  Google Scholar 

  6. Yu, H.R. & Schultz, R.M. Relationship between secreted urokinase plasminogen activator activity and metastatic potential in murine B16 cells transfected with human urokinase sense and antisense genes. Cancer Res. 50, 7623–7633 (1990).

    CAS  PubMed  Google Scholar 

  7. Heiss, M.M. et al. Tumor associated proteolysis and prognosis: new functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system. J. Clin. Oncol. 13, 2084–2093 (1995).

    Article  CAS  Google Scholar 

  8. Pyke, C., Kristensen, P., Ralfkiaer, E., Eriksen, J. & Dano, K. The plasminogen activation system inhuman colon cancer: messenger RNA for the inhibitor PAI-1 is located in endothelial cells in the tumor stroma. Cancer Res. 51, 4067–4071 (1991).

    CAS  PubMed  Google Scholar 

  9. Sier, C.F.M. et al. Inactive urokinase and increased levels of its inhibitor type I in colorectal cancer liver metastasis. Gastroenterology 107, 1449–1456 (1994).

    Article  CAS  Google Scholar 

  10. Liu, G., Shuman, M.A. & Cohen, R.L. Co-expression of urokinase, urokinase receptor and PAI-1 is necessary for optimum invasiveness of cultured lung cancer cells. Int. J. Cancer 60, 501–506 (1995).

    Article  CAS  Google Scholar 

  11. Grondhal-Hansen, J. et al. High levels of urokinase-type plasminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis. Cancer Res. 53, 2513–2521 (1993).

    Google Scholar 

  12. Pedersen, H. et al. Prognostic impact of urokinase, urokinase receptor, and type I plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res. 54, 4671–4675 (1994).

    CAS  PubMed  Google Scholar 

  13. Kuhn, W. et al. Urokinase (uPA) and PAI-1 predict survival in advanced ovarian cancer patients (FICO III) after radical surgery and platinum-based chemotherapy. Gynecol. Oncol. 55, 401–409 (1994).

    Article  CAS  Google Scholar 

  14. Kruithof, E.K., Gudinchet, A. & Bachmann, F. Plasminogen activator inhibitor 1 and plasminogen activator inhibitor 2 in various disease states. Thromb. Haemost. 59, 7–12 (1988).

    Article  CAS  Google Scholar 

  15. Deng, G., Curriden, S.A., Wang, S., Rosenberg, S. & Loskutoff, D.J. Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release? J. Cell Biol. 134, 1–9 (1996).

    Article  Google Scholar 

  16. Chapman, H.A. Plasminogen activators, integrins, and the coordinated regulation of cell adhesion and migration. Curr. Opin. Cell. Biol. 9, 714–724 (1997).

    Article  CAS  Google Scholar 

  17. Fusenig, N.E., Amer, S.M., Boukamp, P. & Worst, K.M. Characteristics of chemically transformed mouse epidermal cells in vitro and in vivo . Bull. Cancer 65, 271–280 (1978).

    CAS  PubMed  Google Scholar 

  18. Carmeliet, P. et al. Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization. J. Clin. Invest. 92, 2746–2755 (1993).

    Article  CAS  Google Scholar 

  19. Carmeliet, P. et al. Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J. Clin. Invest. 92, 2756–2760 (1993).

    Article  CAS  Google Scholar 

  20. DeClerck, P.J., Verstreken, M. & Coolen, D. Immunoassay of murine t-PA, uPA and PAI-1 using monoclonal antibodies raised in gene-inactivated mice. Thomb Haemost. 74, 1305–1309 (1995).

    Article  CAS  Google Scholar 

  21. Lijnen, R.H., Moons, L., Beelen, V., Carmeliet, P. & Collen, D. Biological effects of combined inactivation of plasminogen activator and plasminogen activator inhibitor-1 gene function in mice. Thromb. Haemost. 74, 1126–1131 (1995).

    Article  CAS  Google Scholar 

  22. Nakamura, M. et al. Possible role of plasminogen activator inhibitor 2 in the prevention of the metastasis of gastric cancer tissue. Thromb. Res. 65, 709–719 (1992).

    Article  CAS  Google Scholar 

  23. Nakarda, H. et al. Prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in completely resected gastric cancer. Cancer Res. 54, 2900–2907 (1994).

    Google Scholar 

  24. Foekens, J.A. et al. Plasminogen activator inhibitor-1 and prognosis in primary breast cancer J. Clin. Oncol. 12, 1648–1658 (1994).

    Article  CAS  Google Scholar 

  25. Skobe, M., Rockwell, P., Goldstein, N., Vosseler, S. & Fusenig, N.E. Halting angiogenesis suppresses carcinoma cell invasion. Nature Med. 3, 1222–1227 (1997).

    Article  CAS  Google Scholar 

  26. Bacharach, E., Itin, A. & Keshet, E. In vivo patterns of urokinase and its inhibitor PAI-1 suggest a concerted role in regulating physiological angiogenesis. Proc. Natl. Acad. Sci. USA 89, 10686–10690 (1992).

    Article  CAS  Google Scholar 

  27. Bianchi, E. et al. Immunohistochemical localization of plasminogen activator inhibitor-1 in breast cancer. Int. J. Cancer 60, 597–603 (1995).

    Article  CAS  Google Scholar 

  28. Schnaper, H.W. et al. Plasminogen activators augment endothelial organization in vitro by two distinct pathways. J. Cell. Physiol. 165, 107–118 (1995).

    Article  CAS  Google Scholar 

  29. Montesano, R. et al. Increased proteolytic activity is responsible for the aberrant morphogenetic behavior of endothelial cells expressing the middle T oncogene. Cell 62, 435–445 (1990).

    Article  CAS  Google Scholar 

  30. Pepper, M.S., Sappino, A.P., Montesano, R., Orci, L. & Vassalli, J.-D. Plasminogen activator inhibitor-1 is induced in migrating endothelial cells. J. Cell. Physiol. 153, 129–139 (1992).

    Article  CAS  Google Scholar 

  31. Kanse, S.M., Kost, C., Wilhelm, O.G., Andreasen, P.A. & Preissner, K.T. The urokinase receptor is a major vitronectin-binding protein on endothelial cells. Exp. Cell Res. 224, 344–353 (1996).

    Article  CAS  Google Scholar 

  32. Stefansson, S. & Lawrence, D.A. The serpin PAI-1 inhibits cell migration by blocking integrin αvβ3 binding to vitronectin. Nature 383, 441–443 (1996).

    Article  CAS  Google Scholar 

  33. Waltz, D.A., Natkin, L.R., Fujita, R.M., Wei, Y. & Chapman, H.A. Plasmin and plasminogen activator type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin. J. Clin. Invest. 100, 58–67 (1997).

    Article  CAS  Google Scholar 

  34. Boukamp, P., Stanbridge, E.J., Foo, D.Y., Cerutti, P.A. & Fusenig, N.E. c-Ha-ras oncogene expression in immortalized human keratinocytes (HaCaT) alters growth potential in vivo but lacks correlation with malignancy. Cancer Res. 50, 2840–2847 (1990).

    CAS  Google Scholar 

  35. Fusenig, N.E. in The Keratinocyte Handbook, (eds. Leigh, I., Lane, B., Watt, F.) 71–49 (Cambridge Univ. Press, Cambridge, 1994).

    Google Scholar 

  36. Carmeliet, P., Moons, L., Ploplis, V., Plow, E. & Collen, D. Impaired arterial neointima formation in mice with disruption of the plasminogen gene. J. Clin. Invest. 99, 200–208 (1997).

    Article  CAS  Google Scholar 

  37. Kristensen, P., Pyke, C., Lund, L.R., Andreasen, P.A. & Dano, K. Plasminogen activator inhibitor-type 1 in Lewis lung carcinoma. Histochemistry 93, 559–566 (1990).

    Article  CAS  Google Scholar 

  38. Prendergast, G.C., Diamond, L.E., Dahl, D. &; Cole, M.D. The c-myc-regulated gene mrl encodes plasminogen activator inhibitor 1. Mol. Cell. Biol. 10, 1265–1269 (1990).

    Article  CAS  Google Scholar 

  39. Kristensen, P., Eriksen, J., Blasi, F. & Dano, K. Two alternatively spliced mouse urokinase receptor mRNAs with different histological localisation in the gastrointestinal tract. J. Cell Biol. 115, 1763–1771 (1991).

    Article  CAS  Google Scholar 

  40. de Vries, T.J., Kitson, J.L., Silvers, W.K. & Mintz, B. Expression of plasminogen activators and plasminogen activator inhibitors in cutaneous melanomas of transgenic melanoma-susceptible mice. Cancer Res. 55, 4681–4687 (1995).

    CAS  PubMed  Google Scholar 

  41. Sappino, A.P. et al. Differential protease expression by cutaneous squamous and basal cell carcinomas. J. Clin. Invest. 88, 1073–1079 (1991).

    Article  CAS  Google Scholar 

  42. Carmeliet, P. et al. Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice. Circulation 96, 3180–3191 (1997).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bajou, K., Noël, A., Gerard, R. et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 4, 923–928 (1998). https://doi.org/10.1038/nm0898-923

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0898-923

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing