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Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR): Development of Antagonists of uPA / uPAR Interaction and their Effects In Vitro and In Vivo

[ Vol. 9 , Issue. 19 ]

Author(s):

Ute Reuning, Stefan Sperl, Charlotte Kopitz, Horst Kessler, Achim Kruger, Manfred Schmitt and Viktor Magdolen   Pages 1529 - 1543 ( 15 )

Abstract:


In cancer, increased levels of the tumor-associated serine protease uPA (urokinase-type plasminogen activator) and its receptor uPAR (CD87) are linked to tumor progression, metastasis, and shortened survival in patients afflicted with this disease. Strong clinical and experimental evidence has accumulated that the cell surface interaction of uPA with uPAR facilitates extravasation and intravasation of cancer cells by regulating local proteolysis and attachment of the cells to components of the extracellular matrix. Moreover, the uPA / uPAR system is also implicated in proliferation of some tumor cells and migration of tumor and endothelial cells. Thus, metastasis formation is facilitated via tumor cell spread through the blood circulation system and neovascularization at the metastatic site. This multifunctional potential has rendered the uPA / uPAR system an attractive novel target for anti-metastatic therapy. Consequently, inhibitors of the uPA / uPAR interaction have been and are currently developed for suppression of tumor growth and angiogenesis. In addition to antibodies and recombinant uPA- or uPAR-derived proteins, various linear and cyclic peptides as well as small molecules have been designed and synthesized which potently interfere with the uPA / uPAR interaction, leading to reduced tumor progression in experimental animals. Such compounds affecting the uPA / uPAR system represent novel tumor biology-based therapeutic agents, thereby opening new ways for patient optimized and individualized cancer therapy.

Keywords:

urokinase, urokinase receptor, tumor invasion, cancer therapy, d-amino acid, antagonists

Affiliation:

Klinische Forschergruppe der Frauenklinik, Technische Universitat Munchen, Klinikum rechts der Isar,Ismaninger Str. 22, D-81675 Munchen.



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