Luca Bravi1, Matteo Malinverno1, Federica Pisati1, Noemi Rudini1, Roberto Cuttano1, Roberto Pallini1, Maurizio Martini1, Luigi Maria Larocca1, Marco Locatelli1, Vincenzo Levi1, Giulio Andrea Bertani1, Elisabetta Dejana2, Maria Grazia Lampugnani2. 1. 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.). 2. 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.
Abstract
BACKGROUND AND PURPOSE: 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.
BACKGROUND AND PURPOSE: 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: Sean P Polster; Ying Cao; Timothy Carroll; Kelly Flemming; Romuald Girard; Daniel Hanley; Nicholas Hobson; Helen Kim; James Koenig; Janne Koskimäki; Karen Lane; Jennifer J Majersik; Nichol McBee; Leslie Morrison; Robert Shenkar; Agnieszka Stadnik; Richard E Thompson; Joseph Zabramski; Hussein A Zeineddine; Issam A Awad Journal: Neurosurgery Date: 2019-04-01 Impact factor: 4.654