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Role of plasminogen activator and of 92-KDa type IV collagenase in glioblastoma invasion using an in vitro matrigel model

  • Jasti S. Rao
  • Peter A. Steck
  • Philip Tofilon
  • Douglas Boyd
  • Francis Ali-Osman
  • William G. Stetler-Stevenson
  • Lance A. Liotta
  • Raymond Sawaya

Summary

The invasive nature of human gliomas represents a major factor in preventing their total resection. The exact nature of the underlying mechanisms of tumor cell invasion are still unclear. In this study, we have quantitatively assayed a glioblastoma cell line for its ability to migrate through a polycarbonate filter coated with matrigel which contains a complex of multiple basement membrane components. At 48 h the glioblastoma cell line (U251) showed a rate of invasiveness of 42% and also dependent on the concentration of matrigel. The U251 cell line produced a urokinase type plasminogen activator and a 92-KDa type IV collagenase. Both enzymes were inhibited by the addition of uPA and 92-KDa type IV collagenase antibodies. Those same antibodies reduced the invasion rate of U251 cells from 42% to 12 and 21%, respectively. Similarly, the addition of ε-aminocaproic acid (a plasmin inhibitor) or tissue inhibitor of metalloprotease (TIMP2, a collagenase inhibitor) reduced the invasiveness of U251 cells from 42% to 14% and 10%, respectively. Additionally, the other two glioblastoma cell lines (LG11, UWR1) and astrocytes showed a rate of invasiveness at 41%, 61% and 12%, respectively. Finally, the addition of hyaluronic acid to the matrigel, a constituent of brain extracellular matrix, enhanced the rate of invasion. These findings provide evidence for the role of serine proteases and metalloproteases in facilitating the invasion of extracellular matrix components by glioblastoma cell line and suggest a therapeutic role for protease inhibitors in attempting to minimize the invasive propensity of gliomas.

Key words

glioblastoma invasion matrigel serine proteases metalloproteases serpins tissue inhibitors of metalloproteases 

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Copyright information

© Springer Science+Business Media Dordrecht 1994

Authors and Affiliations

  • Jasti S. Rao
    • 1
  • Peter A. Steck
    • 2
  • Philip Tofilon
    • 3
  • Douglas Boyd
    • 4
  • Francis Ali-Osman
    • 5
  • William G. Stetler-Stevenson
    • 6
  • Lance A. Liotta
    • 6
  • Raymond Sawaya
    • 1
  1. 1.Department of NeurosurgeryThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of Neuro-OncologyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  3. 3.Department of Experimental RadiotherapyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  4. 4.Department of Tumor BiologyThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  5. 5.Department of Experimental PediatricsThe University of Texas M.D. Anderson Cancer CenterHoustonUSA
  6. 6.Laboratory of PathologyNCIBethesdaUSA

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