title: Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial-to-Mesenchymal Transition.
abstract: OBJECTIVE
  Cerebral cavernous malformation (CCM) is characterized by multiple lumen vascular malformations in the central nervous system that can cause neurological symptoms and brain hemorrhages. About 20% of CCM patients have an inherited form of the disease with ubiquitous loss-of-function mutation in any one of 3 genes CCM1, CCM2, and CCM3. The rest of patients develop sporadic vascular lesions histologically similar to those of the inherited form and likely mediated by a biallelic acquired mutation of CCM genes in the brain vasculature. However, the molecular phenotypic features of endothelial cells in CCM lesions in sporadic patients are still poorly described. This information is crucial for a targeted therapy.
  
  
  METHODS
  We used immunofluorescence microscopy and immunohistochemistry to analyze the expression of endothelial-to-mesenchymal transition markers in the cavernoma of sporadic CCM patients in parallel with human familial cavernoma as a reference control.
  
  
  RESULTS
  We report here that endothelial cells, a cell type critically involved in CCM development, undergo endothelial-to-mesenchymal transition in the lesions of sporadic patients. This switch in endothelial phenotype has been described only in genetic CCM patients and in murine models of the disease. In addition, TGF-β/p-Smad- and β-catenin-dependent signaling pathways seem activated in sporadic cavernomas as in familial ones.
  
  
  CONCLUSIONS
  Our findings support the use of common therapeutic strategies for both sporadic and genetic CCM malformations.
authors.affiliation: From the New Strategies to Inhibit Tumor Angiogenesis Program Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, Milan, Italy (L.B., M.M., F.P., N.R., R.C., E.D., M.G.L.); Institute of Neurosurgery (R.P.) and Department of Pathology (M.M., L.M.L.), Università Cattolica Sacro Cuore, Roma; Department of Surgery Division of Neurosurgery, U.O. Neurochirurgia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano (M.L., V.L., G.A.B.); Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden (E.D.); and Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy (M.G.L.).
authors.forename: Luca
authors.initials: L
authors.lastname: Bravi
authors.affiliation: From the New Strategies to Inhibit Tumor Angiogenesis Program Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, Milan, Italy (L.B., M.M., F.P., N.R., R.C., E.D., M.G.L.); Institute of Neurosurgery (R.P.) and Department of Pathology (M.M., L.M.L.), Università Cattolica Sacro Cuore, Roma; Department of Surgery Division of Neurosurgery, U.O. Neurochirurgia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano (M.L., V.L., G.A.B.); Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden (E.D.); and Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy (M.G.L.).
authors.forename: Matteo
authors.initials: M
authors.lastname: Malinverno
authors.affiliation: From the New Strategies to Inhibit Tumor Angiogenesis Program Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, Milan, Italy (L.B., M.M., F.P., N.R., R.C., E.D., M.G.L.); Institute of Neurosurgery (R.P.) and Department of Pathology (M.M., L.M.L.), Università Cattolica Sacro Cuore, Roma; Department of Surgery Division of Neurosurgery, U.O. Neurochirurgia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano (M.L., V.L., G.A.B.); Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden (E.D.); and Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy (M.G.L.).
authors.forename: Federica
authors.initials: F
authors.lastname: Pisati
authors.affiliation: From the New Strategies to Inhibit Tumor Angiogenesis Program Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, Milan, Italy (L.B., M.M., F.P., N.R., R.C., E.D., M.G.L.); Institute of Neurosurgery (R.P.) and Department of Pathology (M.M., L.M.L.), Università Cattolica Sacro Cuore, Roma; Department of Surgery Division of Neurosurgery, U.O. Neurochirurgia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano (M.L., V.L., G.A.B.); Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden (E.D.); and Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy (M.G.L.).
authors.forename: Noemi
authors.initials: N
authors.lastname: Rudini
authors.affiliation: From the New Strategies to Inhibit Tumor Angiogenesis Program Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, Milan, Italy (L.B., M.M., F.P., N.R., R.C., E.D., M.G.L.); Institute of Neurosurgery (R.P.) and Department of Pathology (M.M., L.M.L.), Università Cattolica Sacro Cuore, Roma; Department of Surgery Division of Neurosurgery, U.O. Neurochirurgia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano (M.L., V.L., G.A.B.); Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden (E.D.); and Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy (M.G.L.).
authors.forename: Roberto
authors.initials: R
authors.lastname: Cuttano
authors.affiliation: From the New Strategies to Inhibit Tumor Angiogenesis Program Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, Milan, Italy (L.B., M.M., F.P., N.R., R.C., E.D., M.G.L.); Institute of Neurosurgery (R.P.) and Department of Pathology (M.M., L.M.L.), Università Cattolica Sacro Cuore, Roma; Department of Surgery Division of Neurosurgery, U.O. Neurochirurgia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano (M.L., V.L., G.A.B.); Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden (E.D.); and Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy (M.G.L.).
authors.forename: Roberto
authors.initials: R
authors.lastname: Pallini
authors.affiliation: From the New Strategies to Inhibit Tumor Angiogenesis Program Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, Milan, Italy (L.B., M.M., F.P., N.R., R.C., E.D., M.G.L.); Institute of Neurosurgery (R.P.) and Department of Pathology (M.M., L.M.L.), Università Cattolica Sacro Cuore, Roma; Department of Surgery Division of Neurosurgery, U.O. Neurochirurgia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano (M.L., V.L., G.A.B.); Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden (E.D.); and Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy (M.G.L.).
authors.forename: Maurizio
authors.initials: M
authors.lastname: Martini
authors.affiliation: From the New Strategies to Inhibit Tumor Angiogenesis Program Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, Milan, Italy (L.B., M.M., F.P., N.R., R.C., E.D., M.G.L.); Institute of Neurosurgery (R.P.) and Department of Pathology (M.M., L.M.L.), Università Cattolica Sacro Cuore, Roma; Department of Surgery Division of Neurosurgery, U.O. Neurochirurgia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano (M.L., V.L., G.A.B.); Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden (E.D.); and Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy (M.G.L.).
authors.forename: Luigi Maria
authors.initials: LM
authors.lastname: Larocca
authors.affiliation: From the New Strategies to Inhibit Tumor Angiogenesis Program Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, Milan, Italy (L.B., M.M., F.P., N.R., R.C., E.D., M.G.L.); Institute of Neurosurgery (R.P.) and Department of Pathology (M.M., L.M.L.), Università Cattolica Sacro Cuore, Roma; Department of Surgery Division of Neurosurgery, U.O. Neurochirurgia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano (M.L., V.L., G.A.B.); Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden (E.D.); and Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy (M.G.L.).
authors.forename: Marco
authors.initials: M
authors.lastname: Locatelli
authors.affiliation: From the New Strategies to Inhibit Tumor Angiogenesis Program Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, Milan, Italy (L.B., M.M., F.P., N.R., R.C., E.D., M.G.L.); Institute of Neurosurgery (R.P.) and Department of Pathology (M.M., L.M.L.), Università Cattolica Sacro Cuore, Roma; Department of Surgery Division of Neurosurgery, U.O. Neurochirurgia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano (M.L., V.L., G.A.B.); Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden (E.D.); and Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy (M.G.L.).
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Levi
authors.affiliation: From the New Strategies to Inhibit Tumor Angiogenesis Program Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, Milan, Italy (L.B., M.M., F.P., N.R., R.C., E.D., M.G.L.); Institute of Neurosurgery (R.P.) and Department of Pathology (M.M., L.M.L.), Università Cattolica Sacro Cuore, Roma; Department of Surgery Division of Neurosurgery, U.O. Neurochirurgia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano (M.L., V.L., G.A.B.); Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden (E.D.); and Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy (M.G.L.).
authors.forename: Giulio Andrea
authors.initials: GA
authors.lastname: Bertani
authors.affiliation: From the New Strategies to Inhibit Tumor Angiogenesis Program Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, Milan, Italy (L.B., M.M., F.P., N.R., R.C., E.D., M.G.L.); Institute of Neurosurgery (R.P.) and Department of Pathology (M.M., L.M.L.), Università Cattolica Sacro Cuore, Roma; Department of Surgery Division of Neurosurgery, U.O. Neurochirurgia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano (M.L., V.L., G.A.B.); Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden (E.D.); and Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy (M.G.L.). mariagrazia.lampugnani@ifom.eu elisabetta.dejana@ifom.eu.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.affiliation: From the New Strategies to Inhibit Tumor Angiogenesis Program Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology Fondazione, Milan, Italy (L.B., M.M., F.P., N.R., R.C., E.D., M.G.L.); Institute of Neurosurgery (R.P.) and Department of Pathology (M.M., L.M.L.), Università Cattolica Sacro Cuore, Roma; Department of Surgery Division of Neurosurgery, U.O. Neurochirurgia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano (M.L., V.L., G.A.B.); Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden (E.D.); and Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research, Milan, Italy (M.G.L.). mariagrazia.lampugnani@ifom.eu elisabetta.dejana@ifom.eu.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Lampugnani
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016543:Central Nervous System Neoplasms / Q000473:pathology* / Q000601:surgery; D002648:Child; D004730:Endothelium, Vascular / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000473:pathology* / Q000601:surgery; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
keywords: CCM; EndMT; endothelium; immunohistochemistry; intracranial hemorrhage