title: Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice.
abstract: Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of β-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a β-catenin-driven transcription program that leads to endothelial-to-mesenchymal transition. TGF-β/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate β-catenin transcription activity, reduce vascular malformations in endothelial CCM3-deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas.
authors.affiliation: Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, 20139 Milan, Italy;
authors.forename: Luca
authors.initials: L
authors.lastname: Bravi
authors.affiliation: Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, 20139 Milan, Italy;
authors.forename: Noemi
authors.initials: N
authors.lastname: Rudini
authors.affiliation: Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, 20139 Milan, Italy;
authors.forename: Roberto
authors.initials: R
authors.lastname: Cuttano
authors.affiliation: Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, 20139 Milan, Italy; Department of Biosciences, University of Milan, 20136 Milan, Italy;
authors.forename: Costanza
authors.initials: C
authors.lastname: Giampietro
authors.affiliation: Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, 20139 Milan, Italy;
authors.forename: Luigi
authors.initials: L
authors.lastname: Maddaluno
authors.affiliation: Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, 20139 Milan, Italy;
authors.forename: Luca
authors.initials: L
authors.lastname: Ferrarini
authors.affiliation: Faculty of Medicine, University of Münster, D-48149 Münster, Germany;
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.affiliation: Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, 20139 Milan, Italy;
authors.forename: Monica
authors.initials: M
authors.lastname: Corada
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, UMR-S 740, 75010 Paris, France;
authors.forename: Gwenola
authors.initials: G
authors.lastname: Boulday
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, UMR-S 740, 75010 Paris, France;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tournier-Lasserve
authors.affiliation: Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, 20139 Milan, Italy; Department of Immunology, Genetics and Pathology, Uppsala University, 75185 Uppsala, Sweden; mariagrazia.lampugnani@ifom.eu elisabetta.dejana@ifom.eu.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.affiliation: Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, 20139 Milan, Italy; Mario Negri Institute for Pharmacological Research, 20156 Milan, Italy mariagrazia.lampugnani@ifom.eu elisabetta.dejana@ifom.eu.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Lampugnani
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020786:Hemangioma, Cavernous, Central Nervous System / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C559318:PDCD10 protein, mouse; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D013467:Sulindac; C025462:sulindac sulfide; C025463:sulindac sulfone
keywords: cerebral cavernous malformation; endothelial cells; sulindac metabolites; vascular pathology; β-catenin