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Engineered Antagonists of uPA and PAI-1

  • M. Patrizia Stoppelli
  • Lisbeth M. Andersen
  • Giuseppina Votta
  • Peter A. Andreasen

Abstract

It is now beyond reasonable doubt that plasminogen activation, catalyzed by urokinase-type plasminogen activator (uPA), plays an important role in the growth and dissemination of malignant tumours. The plasmin generated facilitates spread of tumour cells by catalyzing degradation of basement membranes and the extracellular matrix (ECM). In addition, uPA participates in cancer cell-directed tissue remodelling of the surrounding stroma. The function of uPA relies not only on plasmin generation but also on a complex set of pericellular, molecular, and functional interactions with cell surface receptors, adhesion molecules, and ECM proteins. In particular, a delicate balance between uPA and its fast and specific inhibitor, plasminogen activator inhibitor-1 (PAI-1), appears to contribute strongly to tumour dissemination. Here, we review recent advances in engineering compounds inhibiting each of the molecular interactions of uPA and PAI-1. Such compounds include organochemicals, peptides, and monoclonal antibodies, derived by structure-based rational design or directed evolution. Such compounds will help to decipher the tumour biological functions of each molecular interaction of uPA and PAI-1 and provide leads for the eventual use of uPA and PAI-1 as therapeutic targets.

Keywords

Plasminogen Activator Plasminogen Activator Inhibitor Type Plasminogen Activation Urokinase Plasminogen Activator Urokinase Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

ATF

N-terminal uPA fragment

CTRs

Complement-type repeats

ECM

Extracellular matrix

ELISA

Enzyme-linked immunosorbent assay

FPR

Formyl peptide receptor

GFD

Growth factor domain

GPI

Glycosyl phosphatidyl inositol

LDLR

Low-density lipoprotein receptor

MMP

Matrix metalloproteinase

PAI-1

Plasminogen activator inhibitor-1

PI3K

Phosphoinositide 3-kinase

RCL

Reactive centre loop

RNAi

RNA interference

TIMP

Tissue inhibitor of metalloproteases

TTSP

Type-two transmembrane serine protease

tPA

Tissue-type plasminogen activator

uPA

Urokinase-type plasminogen activator

uPAR

Urokinase-type plasminogen activator receptor

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Copyright information

© Springer Science + Business Media, LLC 2008

Authors and Affiliations

  • M. Patrizia Stoppelli
    • 1
  • Lisbeth M. Andersen
    • 2
  • Giuseppina Votta
    • 1
  • Peter A. Andreasen
    • 2
  1. 1.Institute of Genetics and BiophysicsNational Research CouncilVia CastellinoNaplesItaly
  2. 2.Department of Molecular BiologyUniversity of AarhusAarhus CDenmark

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