Abstract
Cerebral cavernous malformation (CCM) is a neurovascular familial or sporadic disease that is characterised by capillary-venous cavernomas, and is due to loss-of-function mutations to any one of three CCM genes. Familial CCM follows a two-hit mechanism similar to that of tumour suppressor genes, while in sporadic cavernomas only a small fraction of endothelial cells shows mutated CCM genes. We reported that in mouse models and in human patients, endothelial cells lining the lesions have different features from the surrounding endothelium, as they express mesenchymal/stem-cell markers. Here we show that cavernomas originate from clonal expansion of few Ccm3-null endothelial cells that express mesenchymal/stem-cell markers. These cells then attract surrounding wild-type endothelial cells, inducing them to express mesenchymal/stem-cell markers and to contribute to cavernoma growth. These characteristics of Ccm3-null cells are reminiscent of the tumour-initiating cells that are responsible for tumour growth. Our data support the concept that CCM has benign tumour characteristics.
Publication types
-
Research Support, Non-U.S. Gov't
-
Video-Audio Media
MeSH terms
-
Animals
-
Apoptosis Regulatory Proteins / genetics*
-
Apoptosis Regulatory Proteins / metabolism
-
Biomarkers / metabolism
-
Brain / blood supply
-
Brain / cytology
-
Brain / pathology
-
Cell Differentiation / genetics
-
Cell Line
-
Central Nervous System Neoplasms / genetics
-
Central Nervous System Neoplasms / pathology*
-
Disease Models, Animal
-
Endothelial Cells / metabolism
-
Endothelial Cells / pathology*
-
Endothelium, Vascular / cytology
-
Endothelium, Vascular / pathology
-
Female
-
Gene Knockout Techniques
-
Hemangioma, Cavernous, Central Nervous System / genetics
-
Hemangioma, Cavernous, Central Nervous System / pathology*
-
Humans
-
Intracellular Signaling Peptides and Proteins / genetics*
-
Intracellular Signaling Peptides and Proteins / metabolism
-
Loss of Function Mutation
-
Membrane Proteins / genetics*
-
Membrane Proteins / metabolism
-
Mesenchymal Stem Cells / metabolism
-
Mice
-
Mice, Knockout
-
Proto-Oncogene Proteins / genetics*
-
Proto-Oncogene Proteins / metabolism
Substances
-
Apoptosis Regulatory Proteins
-
Biomarkers
-
Intracellular Signaling Peptides and Proteins
-
Membrane Proteins
-
PDCD10 protein, human
-
PDCD10 protein, mouse
-
Proto-Oncogene Proteins