Skip to main content
SpringerLink
Log in

Up-regulation of Urokinase-type Plasminogen Activator and its Receptor Correlates with Enhanced Invasion Activity of Human Glioma Cells Mediated by Transforming Growth Factor-α or Basic Fibroblast Growth Factor

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

Abstract

Glioblastoma multiforme is a highly malignant tumor that is extremely refractory to therapy. One reason is its highly invasive nature into brain tissue. Metalloproteinases and their inhibitors, plasminogen activators (PA) and their inhibitors and cathepsins are thought to be involved in invasion by tumor cells. In this study, we determined if the urokinase-type plasminogen activator (uPA) and/or the urokinase-type plasminogen activator receptor (uPAR) were responsible for the invasion activity of a human glioma cell line. We determined the invasion activity of a human glioma U251 cell line using an in vitro invasion assay system. A 2.4- to 5.8-fold increase in invasion activity was observed in the presence of basic fibroblast growth factor (bFGF) or transforming growth factor (TGF)-α. Northern blot analysis showed that bFCF and TGF-α treatment was associated with increases in cellular mRNA levels of uPA and uPAR. Zymographic activity correlated to mRNA levels of uPA and uPAR. Addition of an anti-uPAR monoclonal antibody significantly inhibited the invasion activity induced by bFGF- and TGF-α. Irsogladine, an inhibitor of uPA synthesis, also blocked the invasion activity. These observations suggest that uPA and its receptor have a role in the invasion process of human gliomas.

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. Woolley, DE: Collagenolytic mechanisms in tumor cell invasion. Cancer Metast Rev 3: 361-372, 1984

    Google Scholar 

  2. Reich R, Thompson EW, Iwamoto YY, Martin GR, Deason JR, Fuller GC and Miskin R: Effects of inhibitors of plasminogen activator, serine proteinases, and collagenase IV on the invasion of basement membranes by metastatic cells. Cancer Res 48: 3307-3312, 1988

    Google Scholar 

  3. Ossowski L, Clunie G, Masucci MT and Blasi F: In vivo paracrine interaction between urokinase and its receptor: effect on tumor cell invasion. J Cell Bio 115: 1107-1112, 1991

    Google Scholar 

  4. Abe T, Mori T, Kohno K, Seiki M, Hayakawa T, Welgus HG, Hori S and Kuwano M: Expression of 72 Dka type IV collagenase and invasion activity of human glioma cells. Clin Exp Metast l2: 296-304, 1994

    Google Scholar 

  5. Declerck YA, Perez N, Shimada HH, Boone TC, Langley KE and Taylor SM: Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res 52: 701-708, 1992

    Google Scholar 

  6. Lyons RM, Gentry LE, Purchio AF and Moses HL: Mechanism of activation of latent recombination transforming growth factor beta-1 by plasmin. J Cell Bio 110: 1361-1367, 1990

    Google Scholar 

  7. Giese A and Westphal M: Glioma invasion in the central nervous system. Neurosurgery 39: 235-252, 1990

    Google Scholar 

  8. Lund JM, Engebraaten O, Bjerkvig R and Laerum OD: Invasive glioma cells in tissue culture. Anticancer Res 10: 1135-1151, 1991

    Google Scholar 

  9. DE Ridder L, Laerum OD, Mork SJ and Bigner DD: Invasiveness of human glioma cell lines in vitro: relation to tumorigenicity in athymic mice. Acta Neuropathol 72: 207-213, 1987

    Google Scholar 

  10. Sitrin RG, Gyetko MR, Kole KL, McKeever P and Varani J: Expression of heterogeneous profiles of plasminogen activators and plasminogen activator inhibitors by human glioma lines. Cancer Res 50: 4957-4961, 1990

    Google Scholar 

  11. Murphy P and Hart DA: Modulation of plasminogen activator and plasminogen activator inhibitor expression in the human U373 glioblastoma/astrocytoma cell line by inflammatory mediators, Exp Cell Res 198: 93-100, 1992

    Google Scholar 

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

    Google Scholar 

  13. Blasi F: Urokinase and urokinase receptor: a paracrine/autocrine system regulating cell migration and invasiveness. BioEssay 15: 105-111, 1993

    Google Scholar 

  14. Yamamoto M, Sawaya R, Mohanam S, Rao VH, Bruner JM, Nicolson GL and Rao JS: Expression and localization of urokinase-type plasminogen activator receptor in human gliomas. Cancer Res 54: 5016-5020, 1994

    Google Scholar 

  15. Abe T, Okamura K, Ono M, Kohno K, Mori T, Hori S and Kuwano M: Induction of vascular endothelial tubular morphogenesis by human glioma cells: a model system for tumor angiogenesis. J Clin Invest 92: 54-61, 1993

    Google Scholar 

  16. Takahashi JA, Fukumoto M, Kozai Y, Ito N, Oda Y, Kikuchi H, Hatanaka MA: Inhibition of cell growth and tumorgenesis of human glioblastoma cells by a neutralizing antibody against human basic fibroblast growth factor. FEBS Lett 288, 65-71, 1991

    Google Scholar 

  17. Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR, Vogelstein B: Increased expression of the EGF receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA 84: 6899-6903, 1987

    Google Scholar 

  18. Mizoguchi H, Komiyama S, Matsui K, Hamanaka R, Ono M, Kiue A, Kobayashi M, Shimizu N, Welgus HG and Kuwano M: The response to epidermal growth factor of human maxillary tumor cells in terms of tumor growth, invasion and expression of proteinase inhibitors. Int J Cancer 49: 738-743, 1991

    Google Scholar 

  19. Nakayama Y, Kohno K, Nomura Y, Naito S, Ono M, Shimizu K, Osato K and Kuwano M: Enhanced invasive activity and decreased expression of tissue inhibitors of metalloproteinases by hepatocyte growth factor in human renal cancer cells. The Cancer J 6: 213-2l9, 1993

    Google Scholar 

  20. Hollas W, Blasi F and Boyd D: Role of the urokinase receptor in facilitating extracellular matrix invasion by cultured colon cancer. Cancer Res 57: 3690-3695, 1991

    Google Scholar 

  21. Abe T, Mori T, Wakabayashi Y, Nakagawa M, Cole SPC, Koike K, Kuwano M and Hori S: Expression of multidrug resistance gene in patients with glioma after chemotherapy. J Neuroonc 40: 11-18, 1998

    Google Scholar 

  22. Vecchio SD, Stoppelli MP, Carriero MV, Fonti R, Massa O, Li PY, Botti G, Cerra M, D'Aiuto G, Esposito G and Salvatore M: Human urokinase receptor concentration in malignant and benign breast tumors by in vitro quantitative autoradiograpy: comparison with urokinase levels. Cancer Res 53: 3198-3206, 1993

    Google Scholar 

  23. Soto Y, Morimoto A, Kiue A, Okamura K, Hamanaka R, Kohno K, Kuwano M and Sakata T: Irsogladine is a potent inhibitor of angiogenesis. FEBS Lett 322: 155-158, 1993

    Google Scholar 

  24. Ono M, Kawahara N, Goto D, Wakabayashi Y, Ushiro S, Yamada S, Izumi H, Kuwano M and Sato Y: Inhibition of tumor growth and neovascularization by an anti-gastric ulcer agent, Irsogladine. Cancer Res 56: 1512-1516, 1996

    Google Scholar 

  25. Laiho M and Keski OLJ: Growth factors in the regulation of pericellular proteolysis: a review. Cancer Res 49: 2533-2553, 1990

    Google Scholar 

  26. Haward EW, Bullen EC and Banda MJ: Preferential inhibition of 72-and 92-kDa gelatinases by tissue inhibitor of metalloproteinases-2. J Biol Chem 266: 13070-13075, 1991

    Google Scholar 

  27. Mignatti P and Rifkin DB: Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 73: 161-195, 1993

    Google Scholar 

  28. Bindal AK, Hammound M, Shi WM, Wu SZ, Sawaya R and Rao JS: Prognostic significance of proteolytic enzymes in human brain tumors. J Neuroonc 22: 101-110, 1994

    Google Scholar 

  29. Nakata S, Ito K, Fujimoto K, Kajiwara S, Adachi W, Matsuyama I, Tsuchiya S, Kuwano M and Amano J: Involvement of vascular endothelial growth factor and urokinase-type plasminogen activator receptor in microvessel invasion in human colorectol cancers. Int J Cancer 79: 179-186, 1998

    Google Scholar 

  30. Danø K, Andreasen PA, Grondahl-Hansen J, Kristensen P, Nielsen LS and Skriver L: Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 44: 139-266, 1985

    Google Scholar 

  31. Rømer J, Bugge TH, Pyke C, Lund LR, Flick MJ, Degen JL and Danø K: Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med 2: 287-292, 1996

    Google Scholar 

  32. Ploug M, Rønne E, Behrendet N, Jensen AL, Blasi F and Danø K: Carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidylinositol. J Biol Chem 266: 1926-1933, 1991

    Google Scholar 

  33. Stephens RW, Pollanen J, Tapiovaara H, Leung K-C, Sim P-S, Salonen E-M, Rønne E and Danø K: Activation of pro-urokinase and plasminogen on human sarcoma cells: a proteolytic system with surface-bound reactants. J Cell Biol 108: 1987-1995, 1989

    Google Scholar 

  34. Ellis V, Wun Y-C, Behrendt N, Rønne E and Danø K: Inhibition of receptor-bound urokinase by plasminogen-activator inhibitors. J Biol Chem 265: 9904-9908, 1990

    Google Scholar 

  35. Manchanda N and Schwartz BS: Augmentation of enzymatic activity upon binding to monocytes. J Biol Chem 266: 14580-14584, 1990

    Google Scholar 

  36. Vassalli J-D, Baccino D and Belin D: A cellular binding site for the Mr 55,000 form of the human plasminogen activator, urokinase. J Cell Biol 100: 86-92, 1985

    Google Scholar 

  37. Fazioli F and Blasu F: Urokinase-type plasminogen activator and its receptor: new targets for anti-metastatic theraphy? Trends Pharmacol Sci 15: 25-29, 1994

    Google Scholar 

  38. Nayakama Y, Okazaki K, Shibao T, Hirata K, Nagata N, Kuwano M and Itoh K: Alternative expression of the collagenase and adhesion molecules in the highly metastatic clones of human colonic cancer cell lines. Clin Exp Metast 16: 461-469, 1998

    Google Scholar 

  39. Pepper MS, Vassalli J-D, Montesano R and Orct L: Urokinase-type plasminogen activator is induced in migrating capillary endothelial cells. J Cell Biol 105: 2535-2541, 1987

    Google Scholar 

  40. Sato Y, Okamura K, Morimoto A, Hamanaka R, Hamaguchi K, Shimada T, Ono M, Kohno K, Sakata T and Kuwano M: Indispensable role of tissue-type plasminogen activator in the growth factor-dependent tube formation of human microvascular endothelial cells in vitro. Expt Cell Res. 204: 223-229, 1993

    Google Scholar 

  41. Ushiro S, Mizoguchi K, Yoshida S, Jimi S, Fujiwara T, Yoshida M, Wei ET, Kitabgi P, Amagaya S, Ono M and Kuwano M: Stimulation of cell-surface urokinase-type plasminogen activator activity and cell migration in vascular endothelial cells by a novel hexapeptide analogue of neurotensin. FEBS Lett 418: 341-345, 1997

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Oita Medical University, Hasama-mati, Oita, Japan

    Teruaki Mori, Tatsuya Abe, Yukihiro Wakabayashi, Takamitsu Hikawa & Shigeaki Hori

  2. Laboratory of Anticancer Drug Research, Taiho Pharmaceutical Co., Saitama, Japan

    Ken-ichi Matsuo & Yuji Yamada

  3. Department of Biochemistry, Kyushu University School of Medicine, Fukuoka, Japan

    Michihiko Kuwano

Authors
  1. Teruaki Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tatsuya Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yukihiro Wakabayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takamitsu Hikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ken-ichi Matsuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuji Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michihiko Kuwano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shigeaki Hori
    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

Mori, T., Abe, T., Wakabayashi, Y. et al. Up-regulation of Urokinase-type Plasminogen Activator and its Receptor Correlates with Enhanced Invasion Activity of Human Glioma Cells Mediated by Transforming Growth Factor-α or Basic Fibroblast Growth Factor. J Neurooncol 46, 115–123 (2000). https://doi.org/10.1023/A:1006339717748

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006339717748

Search

Navigation