Fiche publication
Date publication
juillet 2019
Journal
Matrix biology : journal of the International Society for Matrix Biology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr AVEROUS Gerlinde
,
Pr CHENARD Marie-Pierre
,
Dr LEFEBVRE Olivier
,
Pr MATHELIN Carole
,
Dr OREND Gertraud
,
Dr MANGIN Pierre
Tous les auteurs :
Sun Z, Velázquez-Quesada I, Murdamoothoo D, Ahowesso C, Yilmaz A, Spenlé C, Averous G, Erne W, Oberndorfer F, Oszwald A, Kain R, Bourdon C, Mangin P, Deligne C, Midwood K, Abou-Faycal C, Lefebvre O, Klein A, van der Heyden M, Chenard MP, Christofori G, Mathelin C, Loustau T, Hussenet T, Orend G
Lien Pubmed
Résumé
Metastasis is a major cause of death in cancer patients. The extracellular matrix molecule tenascin-C is a known promoter of metastasis, however the underlying mechanisms are not well understood. To further analyze the impact of tenascin-C on cancer progression we generated MMTV-NeuNT mice that develop spontaneous mammary tumors, on a tenascin-C knockout background. We also developed a syngeneic orthotopic model in which tumor cells derived from a MMTV-NeuNT tumor. Tumor cells were transfected with control shRNA or with shRNA to knockdown tenascin-C expression and, were grafted into the mammary gland of immune competent, wildtype or tenascin-C knockout mice. We show that stromal-derived TNC increases metastasis by reducing apoptosis and inducing the cellular plasticity of cancer cells located in pulmonary blood vessels invasions (BVI), before extravasation. We characterized BVI as organized structures of tightly packed aggregates of proliferating tumor cells with epithelial characteristics, surrounded by Fsp1+ cells, internally located platelets and, a luminal monolayer of endothelial cells. We found extracellular matrix, in particular, tenascin-C, between the stromal cells and the tumor cell cluster. In mice lacking stromal-derived tenascin-C, the organization of pulmonary BVI was significantly affected, revealing novel functions of host-derived tenascin-C in supporting the integrity of the endothelial cell coat, increasing platelet abundance, tumor cell survival, epithelial plasticity, thereby promoting overall lung metastasis. Many effects of tenascin-C observed in BVI including enhancement of cellular plasticity, survival and migration, could be explained by activation of TGF-β signaling. Finally, in several human cancers, we also observed BVI to be surrounded by an endothelial monolayer and to express tenascin-C. Expression of tenascin-C is specific to BVI and is not observed in lymphatic vascular invasions frequent in breast cancer, which lack an endothelial lining. Given that BVI have prognostic significance for many tumor types, such as shorter cancer patient survival, increased metastasis, vessel occlusion, and organ failure, our data revealing a novel mechanism by which stromal tenascin-C promotes metastasis in human cancer, may have potential for diagnosis and therapy.
Mots clés
Blood vessel invasions, Cellular plasticity, Circulating tumor cells, Endothelial cells, Endothelialization, Fsp1+ cells, Lung metastasis, TGF-β signaling, Tenascin-C, Tumor emboli
Référence
Matrix Biol.. 2019 Jul 6;:
