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Rôle de la thrombospondine 1 dans la progression et la dissémination du cancer du sein

Abstract : Metastasis are responsible for 90% of cases of patients death and so represent a major therapeutic challenge in oncology. Anti-angiogenic treatments, which inhibit tumor vascularization and increase hypoxia, have limited clinical efficiency. This inefficiency could be a consequence of hypoxia. Indeed, links have been established between hypoxia and: metabolic changes in tumor cells, increase in cancer stem cells, epithelial-mesenchymal transition and resistance to treatment. Experimental and clinical evidence also suggest that hypoxia may directly induce metastatic dissemination. These observations led us to reassess the role of hypoxia in metastatic dissemination by focusing on the study of the first identified endogenous angiogenic inhibitor, the Thrombospondin 1 (TSP1). TSP1 is also an activator of latent TGFbéta. The aim of this work was to study the role of TSP1 in tumor progression and dissemination of metastatic breast cancer. In clinic, we observed that the expression of TSP1 is correlated with markers of aggressiveness and that it increases with tumor grade. In an orthotopic model of metastatic breast tumors, we have shown that inhibition of TSP1 strongly reduce EMT, invasion and lung metastasis meanwhile the vascularization of the primary tumor is densified and more functional, thus reducing hypoxia. To determine the role of TSP1 in the occurrence of metastasis, we generate point mutations of this gene in TGFbéta activation domain or in the binding domain to CD36 that predominantly mediates the anti-angiogenic properties of TSP1. Mutations of either of these sequences result in a drastic decrease in lung metastasis, which confirms the importance of TGFbéta in metastatic dissemination. Our results also demonstrate a direct link between hypoxia and metastasis: the inactivation of anti-angiogenic properties of TSP1, which increases tumor perfusion and decreases hypoxia without affecting primary tumor growth, blocks metastatic dissemination even though the cells have the ability to migrate. This work led us to propose a new therapeutic concept aiming to normalize tumor vascularization and reduce hypoxia by an "anti-antiangiogenic" strategy based on TSP1 inhibition. This strategy should inhibit metastatic spreading, promote the diffusion of chemotherapeutic treatments and increase the efficiency of radiotherapy, dependent on oxygen presence.
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Julie Tenet. Rôle de la thrombospondine 1 dans la progression et la dissémination du cancer du sein. Cancer. Université Paul Sabatier - Toulouse III, 2016. Français. ⟨NNT : 2016TOU30328⟩. ⟨tel-01701316⟩

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