Objectif Degradation of the extracellular matrix and basement membranes plays a crucial role in cancer invasion and metastasis. This degradation is accomplished by the concerted action of several extracellular proteolytic enzyme-systems. The objective of the present proposal is to contribute to a clarification of molecular mechanisms of extracellular proteolysis by defining the interaction between the various enzyme systems in cancer invasion, the ultimate goal being to create the basis for a rational approach to anti-invasive and anti-metastatic therapy, which may result in increased survival and quality of life for cancer patients.The most important of the proteolytic enzymes involved in cancer invasion belong to the families of matrix metalloproteinases (several types of collagenases and stromelysins) and serene proteinases (the plasminogen activator uPA). The activity of these enzymes is finely regulated by proenzyme activation, specific inhibitors and cell surface receptors. These extracellular proteolytic enzyme systems are also involved in matrix degradation in non-neoplastic tissue remodelling processes. The main difference between the neoplastic and non-neoplastic processes appears in this respect to be in the regulation of the expression of the various components. Many of these enzyme systems are very well characterised. The partners in the proposed project are all among the internationally leading in the field of extracellular proteolysis and cancer, and have typically contributed by in depth studies of one or two of the enzymes or enzyme systems. Recent studies, in the partners' laboratories and elsewhere, on the biochemistry and expression of components of these enzyme systems indicate that there is strong interaction and cooperativity between the systems, and particularly results obtained by targeted gene disruption in transgenic mice suggest that there is a functional overlap between the individual systems. Inhibition of matrix degrading enzyme systems is an attractive new approach to anti-invasive and anti-metastatic therapy, and some drugs with this effect are currently being investigated in clinical trials. The functional overlap between individual enzyme systems, discussed above however indicates that such a therapy, in order to be effective, requires that two or more of the systems are inhibited. In order to provide a rational basis for such a combined therapy, it is necessary that the interactions and functional overlaps between the individual proteolytic systems are exactly defined. The objectives of the present proposal are to combine the expertise of the individual partners in the individual enzyme systems in a concerted effort to obtain this goal. These objectives comply precisely with the objectives of the BIOMED 2 work programme 4.1.1. as to define molecular mechanisms of cancer metastasis. It will be achieved by : analysis of the molecular mechanisms controlling co-ordinate gene expression of components of extracellular proteolytic enzyme systems during invasion and by biochemical analysis of interaction between matrix proteinase systems. Evaluation of the interaction of matrix proteinase systems in physiological events and cancer invasion and metastasis will be carried out as well as evaluation of prognostic and therapeutic aspects of interaction between extracellular proteolytic enzyme systems in cancer. A search for novel molecules involved in extracellular proteolysis in cancer invasion and metastasis is proposed. Champ scientifique medical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programme(s) FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998 Thème(s) 4.1.1 - Mechanism of tumorigenesis and metastasis Appel à propositions Data not available Régime de financement CSC - Cost-sharing contracts Coordinateur Rigshospitalet Krbenhavn Contribution de l’UE Aucune donnée Adresse 49,Strandboulevarden 2100 Copenhagen Danemark Voir sur la carte Coût total Aucune donnée Participants (5) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire Centre National de la Recherche Scientifique France Contribution de l’UE Aucune donnée Adresse 11,Rue Humann 67085 Strasbourg Voir sur la carte Coût total Aucune donnée FONDAZIONE CENTRO SAN RAFFAELE DEL MONTE TABOR - ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO Italie Contribution de l’UE Aucune donnée Adresse Via Olgettina 58 20132 MILANO Voir sur la carte Coût total Aucune donnée Karolinska Institute Suède Contribution de l’UE Aucune donnée Adresse 9,Karolinska Instituttet 171 77 Stockholm Voir sur la carte Coût total Aucune donnée Universidad de Oviedo Espagne Contribution de l’UE Aucune donnée Adresse S/N,Julian Claveria 33006 Ovidod Voir sur la carte Coût total Aucune donnée University of East Anglia Royaume-Uni Contribution de l’UE Aucune donnée Adresse Wort's Causeway CB1 4RN Cambridge Voir sur la carte Coût total Aucune donnée
