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.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
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
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2008 Springer Science + Business Media, LLC
About this chapter
Cite this chapter
Stoppelli, M.P., Andersen, L.M., Votta, G., Andreasen, P.A. (2008). Engineered Antagonists of uPA and PAI-1. In: Edwards, D., Høyer-Hansen, G., Blasi, F., Sloane, B.F. (eds) The Cancer Degradome. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69057-5_35
Download citation
DOI: https://doi.org/10.1007/978-0-387-69057-5_35
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-387-69056-8
Online ISBN: 978-0-387-69057-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)