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Urokinasetyp-Plasminogenaktivator (uPA), sein Inhibitor PAI-1 und sein Rezeptor (CD87) sind an Tumorinvasion und Metastasierung solider maligner Tumoren beteiligt

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Malignome und Hämostase

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Zusammenfassung

Extravasation und Intravasation von Tumorzellen in soliden malignen Tumoren erfolgt in 3 verschiedenen Schritten:

  • Anheftung an und Interaktion von Tumorzellen mit Komponenten der Basalmembran und der extrazellulären Matrix,

  • lokale Proteolyse und

  • Tumorzellmigration.

Verschiedene Klassen von Proteasen, deren Inhibitoren und Rezeptoren sind an Tumorinvasion und Metastasierung beteiligt. Es sind dies:

  • Matrixmetalloproteasen; zu denen zählen die Kollagenasen, Gelatinasen und Stromelysine.

  • Cysteinproteasen; z.B. Cathepsine B und L.

  • Aspartylprotease Cathepsin D.

  • Serinproteasen; dazu zählen Plasmin, Gewebetyp-Plasminogenaktivator (tPA) und der Urokinasetyp-Plasminogenaktivator (uPA).

Die klinische Relevanz von Proteasen wurde in den letzten Jahren besonders für uPA und seinen Inhibitor PAI-1 gezeigt. uPA und PAI-1 sind starke, unabhängige prognostische Faktoren für die Rezidivhäufigkeit und/oder die Überlebenswahrscheinlichkeit bei Patientinnen mit Brustkrebs, Eierstockkrebs, Lungenkrebs, Nierenkrebs und malignen Erkrankungen des Gastrointestinaltrakts (Magen, Kolon, Ösophagus). Die starke Korrelation zwischen erhöhten uPA- und/oder PAI-1-Werten in Primärtumorgeweben und des malignen Phänotyps von Tumorzellen führte zur Entwicklung neuer, an der Tumorbiologie orientierten Konzepten, mit dem Ziel, die Expression des uPA oder des uPA-Rezeptors (CD 87) zu unterdrücken bzw. die Interaktion von uPA mit dem uPA-Rezeptor zu verhindern. Zu diesen Konzepten zählen gegen uPA oder uPAR gerichtete Antisense-Oligonukleotide und Antikörper, gegen das enzymatische Zentrum von uPA gerichtete Inhibitoren und rekombinante oder synthetische uPA und CD 87-Analoga.

Danksagungen. Diese Arbeit wurde von der Deutschen Forschungsgemeinschaft (Klinische Forschergruppe GR280/4−1 und GR280/4−2) unterstützt. Die Autoren danken Dr. R. Hart, American Diagnostica, Greenwich, CT, USA, herzlich für die großzügige materielle Unterstützung.

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Authors
  1. M. Schmitt
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  2. O. Wilhelm
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  3. V. Magdolen
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  4. U. Reuning
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  5. L. Goretzki
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  6. C. Thomssen
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  7. W. Kuhn
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  8. U. Weidle
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  9. F. Jänicke
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  10. H. Graeff
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Editors and Affiliations

  1. Boehringer Mannheim, Sandhofer Str. 116, 68305, Mannheim, Deutschland

    Eberhard Spanuth

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Schmitt, M. et al. (1996). Urokinasetyp-Plasminogenaktivator (uPA), sein Inhibitor PAI-1 und sein Rezeptor (CD87) sind an Tumorinvasion und Metastasierung solider maligner Tumoren beteiligt. In: Spanuth, E. (eds) Malignome und Hämostase. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-79744-6_16

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