Skip to main content
SpringerLink
Log in

Prognostic significance of proteolytic enzymes in human brain tumors

  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Summary

Proteases and their inhibitors have been shown to play roles in tumor invasion and metastasis in a number of experimental models. Recently, relative increases in the amounts of urokinase type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in tumor samples have been correlated with poorer pathological grade, shorter disease-free interval, and shorter survival. To date, all studies investigating the prognostic significance of proteases and their inhibitors have been limited to extracranial cancer. In this article, we review the literature and present our data on the prognostic significance of proteases in human brain tumors. High levels of uPA were seen in malignant glioma and metastatic tumors (n=82), whereas normal levels of uPA were found in low-grade gliomas. Analysis with magnetic resonance imaging (MRI) demonstrated a significant correlation between high levels of uPA and necrosis and edema (n=50; P < 0.05). Similarly, patients with high levels of uPA had shorter survival than did patients with low levels of uPA.

Tissue-type plasminogen activator (tPA), which was virtually absent in glioblastoma multiforme (GBM), colon, lung, and breast metastasis, was found in normal quantities in anaplastic astrocytoma (AA), low-grade glioma (LGG), and meningioma. Melanoma had significantly more tPA activity than normal brain did. A reverse correlation was found between tPA and MRI findings of necrosis, enhancement, and edema. Similarly, patients with no detectable tPA activity had shorter survival than did patients with detectable tPA activity. We conclude that high levels of uPA and absent tPA activity correlate with histologically malignant brain tumors, aggressive characteristics, and shorter survival.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kelly PJ, Daumas-Duport C, Kispert DB, Kall BA, Scheithauer BW, Illig JJ: Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg 66: 865–874, 1987

    PubMed  Google Scholar 

  2. Pederson PH, Marienhagen K, Mork S, Bjerkvig R: Migratory pattern of fetal rat brain cells and human glioma cells in the adult rat brain. Cancer Res 53: 5158–5165, 1993

    PubMed  Google Scholar 

  3. Liotta LA, Steeg PS, Stetler-Stevenson WG: Cancer metastasis and angiogenesis: An imbalance of positive and negative regulation. Cell 64: 327–336, 1991

    Google Scholar 

  4. Ellis V, Danø K: Plasminogen activation by receptor-bound urokinase. Semin Thromb Haemostat 17: 194–200, 1991

    Google Scholar 

  5. Mohanam S, Sawaya R, McCutcheon I, Ali-Osman F, Boyd D, Rao JS: Modulation ofin vitro invasion of human glioblastoma cells by urokinase-type plasminogen activator receptor antibody. Cancer Res 53: 4143–4147, 1993

    PubMed  Google Scholar 

  6. Andreasen PA, Nielsen LS, Kristensen P, Grondahl-Hansen J, Skriver L, Danø K: Plasminogen activator inhibitor from human fibrosarcoma cells binds urokinase-type plasminogen activator, but not its proenzyme. J Biol Chem 261: 7644–7651, 1986

    PubMed  Google Scholar 

  7. Cubellis MV, Andreasen P, Ragno P, Mayer M, Danø K, Blasi F: Accessibility of receptor-bound urokinase to type-1 plasminogen activator inhibitor. Proc Natl Acad Sci USA 86: 4828–4832, 1989

    PubMed  Google Scholar 

  8. Olson D, Pollanen J, Hoyer-Hansen G, Ronne E, Sakaguchi K, Wun TC, Apella E, Danø K, Blasi F: Internalization of the urokinase: Plasminogen activator inhibitor type-1 complex is mediated by the urokinase receptor. J Bio Chem 267: 9129–9133, 1992

    Google Scholar 

  9. Ossowski L, Reich E: Antibodies to plasminogen activator inhibit human tumor metastasis. Cell 35: 611–619, 1983

    PubMed  Google Scholar 

  10. Achbarou A, Kaiser S, Tremblay G, Ste-Marie LG, Brodt P, Goltzman D, Rabbani SA: Urokinase over production results in increased skeletal metastasis by prostate cancer cellsin vivo. Cancer Res 54: 2372–2377, 1994

    PubMed  Google Scholar 

  11. Pyke C, Kirstensen P, Ralfkiaer E, Eriksen J, Danø K: The plasminogen activation system in human colon cancer: Messenger RNA for the inhibitor PAI-1 is located in endothelial cells in the tumor stroma. Cancer Res 51: 4067–4071, 1991

    PubMed  Google Scholar 

  12. Danø K, Andreasen PA, Grondahl-Hansen J, Kristensen P, Nielsen LS, Skriver L: Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 44: 139–266, 1984

    Google Scholar 

  13. Ausprunk DH, Folkman J: Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during angiogenesis. Microvasc Res 14: 53–65, 1977

    PubMed  Google Scholar 

  14. Reilly D, Christensen L, O'Sullivan C, O'Higgins N, Fennelly JJ, Andreasen PA: Type 1 plasminogen activator inhibitor in human breast carcinomas. Int J Cancer 50: 208–214, 1992

    PubMed  Google Scholar 

  15. Alvord EC Jr: Is necrosis helpful in the grading of gliomas? Editorial opinion. J Neuropathol Exp Neurol 51: 127–132, 1992

    PubMed  Google Scholar 

  16. Nelson JS, Tsukada Y, Schoenfeld D, Fulling K, Lamarche J, Peress N: Necrosis as a prognostic criterion in malignant supratentorial astrocytric gliomas. Cancer 52: 550–554, 1983

    PubMed  Google Scholar 

  17. Sawaya R: The fibrinolytic enzymes in the biology of brain tumors. In: Sawaya R (ed) Fibrinolysis and the Central Nervous System. Hanley and Belfus, Inc., Philadelphia, 1990, pp 106–126

    Google Scholar 

  18. Sawaya R, Rämö J, Shi ML, Mandybur G: Biological significance of tissue plasminogen activator content in brain tumors. J Neurosurg 74: 480–486, 1991

    PubMed  Google Scholar 

  19. Sawaya R, Yamamoto M, Ramo OJ, Shi ML, Rao JS: Plasminogen activator inhibitor-1 in brain tumors: Relation to malignancy and necrosis. Neurosurgery (in press), 1994

  20. Colucci M, Parmo JA, Collen D: Inhibition of one-chain and two-chain forms of human tissue-type plasminogen activator by the fast-acting inhibitor of plasminogen activatorin vitro andin vivo. J Lab Clin Med 198: 53–59, 1986

    Google Scholar 

  21. Medcalf RL, Kruithof EKO, Schleuning WF: Plasminogen activator inhibitor 1 and 2 are tumor necrosis factor/cachectin-responsive genes. J Exp Med 168: 751–759, 1988

    PubMed  Google Scholar 

  22. van Hinsbergh VWM, Kooistra T, van den Berg EA, Princen HM, Fiers W, Emeis JJ: Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cellsin vitro and in ratsin vivo. Blood 72: 1467–1473, 1988

    PubMed  Google Scholar 

  23. Engel U: The morphology of hemostasis failure in glial brain tumors. Acta Histochem (Suppl) 42: 201–210, 1992

    Google Scholar 

  24. Caillé JM, Guibert-Tranier F, Calabet A, Billerey J, Piton J: Abnormal enhancements after contrast injection. In: Caillé JM, Salmon G (eds) Computerized Tomography. Springer, Berlin, 1980, pp 166–171

    Google Scholar 

  25. Nyström S: Pathological changes in blood vessels of human glioblastoma multiforme. Comparative studies using plastic casting, angiography, light microscopy, and electron microscopy, and with reference to some other brain tumors. Acta Pathol Microbiol 49 (Suppl): 137, 1960

    Google Scholar 

  26. Long DM: Capillary ultrastructure and the blood-brain barrier in human malignant brain tumors. J Neurosurg 32: 127–144, 1970

    PubMed  Google Scholar 

  27. Pepper MS, Belin D, Montesano R, Orci L, Vassalli JD: Transforming growth factor-beta 1 modulates basic fibroblast growth factor-induced proteolytic and angiogenic properties of endothelial cellsin vitro. J Cell Biol 11: 743–755, 1990

    Google Scholar 

  28. Quindlen EA, Bucher PB: Correlation of tumor plasminogen activator with peritumoral cerebral edema. J Neurosurg 66: 729–733, 1987

    PubMed  Google Scholar 

  29. Unterberg A, Baethmann AJ: The kallikrein-kinin system as mediator in vasogenic brain edema. Part 1: Cerebral exposure to bradykinin and plasma. J Neurosurg 61: 87–96, 1984

    PubMed  Google Scholar 

  30. Maier-Hauff K, Baethmann AJ, Lange M, Schürer L, Unterberg A: The Kauikrien-Kinin system as a mediator in vasogenic brain edema. J Neurosurg 61: 97–106, 1984

    PubMed  Google Scholar 

  31. Duffy MJ, Reilly D, O'Sullivan C, O'Higgins N, Fennelly JJ, Andreasen P: Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer. Cancer Res 50: 6827–6829, 1990

    PubMed  Google Scholar 

  32. Grondahl-Hansen J, Christensen U, Rosenquist C, Brunner N, Mouridsen HT, Danø K, Blichert-Toft M: 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

    PubMed  Google Scholar 

  33. Foekens JA, Schmitt M, van Putten WLJ, Peters HA, Bontenbal M, Janicke F, Klijn JGM: Prognostic value of urokinase-type plasminogen activator in 671 primary breast cancer patients. Cancer Res 52: 6101–6105, 1992

    PubMed  Google Scholar 

  34. Kono S, Rao JS, Bruner JM, Sawaya R: Immunohistochemical localization of plasminogen activator inhibitors-1 (PAI-1) in human brain tumors. J Neuropathol Exp Neurology 53: 256–262, 1994

    Google Scholar 

  35. Yamamoto M, Sawaya R, Loskutoff DJ, Bruner JM, Oka K, Tomonaga M, Nicolson GL, Rao JS: Expression and cellular localization of messenger RNA for plasminogen activator inhibitor type-1 in human astrocytomasin vivo. Cancer Res 54: 3329–3332, 1994

    PubMed  Google Scholar 

  36. Oka T, Ishida T, Nishino T, Sugimachi K: Immunohistochemical evidence of urokinase-type plasminogen activator in primary and metastatic tumors of pulmonary adenocarcinoma. Cancer Res 51: 3522–3525, 1991

    PubMed  Google Scholar 

  37. Frank AJ, Ellis E: Immunohistochemical localization of tissue plasminogen activator in human brain tumors. Br J Cancer 59: 462–466, 1989

    PubMed  Google Scholar 

  38. Pedersen H, Grondahl-Hansen J, Francis DKO, Hansen HH, Danø K, Brunner N: Urokinase and plasminogen activator inhibitor type 1 in pulmonary adenocarcinoma. Cancer Res 54: 120–123, 1994

    PubMed  Google Scholar 

  39. Landau BJ, Kwaan HC, Verrusio EN, Brem SS: Elevated levels of urokinase-type plasminogen activator and plasminogen activator inhibitor type-1 in malignant brain tumor. Cancer Res 54: 1105–1108, 1994

    PubMed  Google Scholar 

  40. Rutka JT, Myatt CA, Giblin JR, Davis RL, Rosenblum ML: Distribution of extracellular matrix proteins in primary human brain tumors: An immunohistochemical analysis. Can J Neurol Sci 14: 25–30, 1987

    PubMed  Google Scholar 

  41. Gladson CL, Cheresh DA: Glioblastoma expression of vitronectin and the a2b3 integrin. J Clin Invest 88: 1924–1932, 1991

    PubMed  Google Scholar 

  42. Yamamoto M, Sawaya R, Mohanam S, Bindal AK, Bruner JM, Oka K, Rao VH, Tomonaga M, Nicolson GL, Rao JS: Expression and localization of urokinase-type plasminogen activator in human astrocytomasin vivo. Cancer Res 54: 3654–3661, 1994

    Google Scholar 

  43. Russel DC, Rubinstain LJ: Pathology of tumors of the nervous system (5th ed), Williams & Wilkins, Baltimore, 1989

    Google Scholar 

  44. Roblin R, Young PL: Dexamethasone regulation of plasminogen activator in embryonic and tumor-derived human cells. Cancer Res 40: 2706–2713, 1980

    PubMed  Google Scholar 

  45. Coleman PL, Patel PD, Cwikel BJ, Rafferty UM: Characterization of the dexamethasone-induced inhibitor of plasminogen activator in HTC hepatoma cells. J Biol Chem 261: 4352–4357, 1986

    PubMed  Google Scholar 

  46. Laug WE: Glucocorticoids inhibit plasminogen activator production by endothelial cells. Thromb Haemostat 50: 888–892, 1983

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, 77030, Houston, Texas, USA

    Ajay K. Bindal, Maarouf Hammoud, Wei Ming Shi, Shi Z. Wu, Raymond Sawaya & Jasti S. Rao

Authors
  1. Ajay K. Bindal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maarouf Hammoud
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Ming Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shi Z. Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Raymond Sawaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jasti S. Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bindal, A.K., Hammoud, M., Shi, W.M. et al. Prognostic significance of proteolytic enzymes in human brain tumors. J Neuro-Oncol 22, 101–110 (1994). https://doi.org/10.1007/BF01052886

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01052886

Key words

Search

Navigation