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. © 2008 Springer Science + Business Media, LLC.
Engineered antagonists of uPA and PAI-1
Stoppelli, Maria Patrizia;
2008-01-01
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. © 2008 Springer Science + Business Media, LLC.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
