TSP THROMBOSE CANCER · Contribution de la TSP-1 dans l hémostase, l" angiogénèse et la dissémination métastatique"

Final Activity Report Summary - TSP THROMBOSE CANCER (Contribution de la TSP-1 dans l'hemostase, l'angiogenese et la dissemination metastatique)

My project aimed at validating a strategy consisting of the neutralisation of a vascular glycoprotein, namely Thrombospondin-1 (TSP-1), as a pharmacological approach for the treatment of thrombosis, and at developing an anti-cancer therapy based on the properties of TSP-1 in metastasis and angiogenesis. In the continuity of my postdoctoral research, and in close collaboration with my postdoctoral host, I studied the contribution of TSP-1 in platelet recruitment onto vessel wall in two ways: 1. in vivo, with the use of TSP-1 null mice in models of inflammation and thrombosis monitored in situ by intravital epifluorescence videomicroscopy; 2. in vitro, with the identification of cell receptors and adhesive protein interacting with TSP-1 and mediating TSP-1 functions in platelet adhesion and aggregation. We therefore demonstrated that TSP-1 was capable of controlling vascular platelet recruitment and thrombus adherence by protecting the endothelial or sub-endothelial von Willebrand factor from cleavage by ADAMTS13 metalloprotease enzyme. The related paper was published in the February 2006 issue of Blood journal. Platelets were favouring metastasis by participating in tumour cells adhesion and extravasation through the vessel wall. Since TSP-1 was a major platelet-granule component, we wanted to investigate the role of TSP-1 in tumourigenesis and metastasis. For this purpose we firstly developed an in vivo metastasis' model based on the non-invasive measurement of bioluminescence emitted by B16F10 murine melanoma cells expressing the firefly luciferase protein. The description of the model and the characterisation of the B16F10 cell clone were submitted for publication in Clinical and Experimental Metastasis by the time of the project completion. TSP-1 null mice with a C57BL/6 backround syngeneic with the B16F10 cells were bred in the animal facility of the Haematology University Institute and were to be tested in this model. Meanwhile, the model was used by other researchers of the U553 laboratory. In parallel to these studies, two collaborative works were engaged to study the involvement of TSP-1 in endothelial progenitor cells recruitment to injured vessel wall, in collaboration with Dr O Blanc-Brude at INSERM U689, as well as to angiogenesis. The first study was under process while the second was accepted for publication in experimental cell research by the end of the funded project. Shortly after joining the Institut National de la Recherche et de la Sante Medicale (INSERM) U553, and coming first in chronological order, I initiated the development of an intravital videomicroscopy work station at U553 and used it in the context of a pre-existing research project led by Dr Francoise Fauvel-Lafeve, in order to quickly launch my activities and favour my integration within the group. This work led to the publication of an article in the January 2006 issue of Vascular Pharmacology, in which we described the in vivo antithrombotic properties of the type III collagen-related peptide kogeogpk. Meanwhile, ongoing collaborations with Dr Marc Hoylaerts from the Centre for Molecular and Muscular Biology (CMVB) of the Katholieke Universiteit Leuven, Belgium, led to the recent publication, in the October 2006 issue of the Journal of Thrombosis and Haemostasis, of a work throwing new lights on the interactions between von Willebrand factor and fibrillar collagen, with implications in the pathogenesis of thrombosis.

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