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.
Highlights
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
This is in agreement with the human disease, where following a double-hit process[6,7,8,9], a few heterozygote endothelial cells acquire homozygosity for the Ccm gene inactivation and trigger the formation of cavernomas
An important event in the evolution of the cavernomas appears to be the attraction of Ccm3+/+ cells by Ccm3−/− cells, which, in turn, strongly contribute to the growth of the malformation
Summary
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. We show here that cavernomas originate from clonal expansion of a small number of Ccm3−/− endothelial cells that express EndMT and progenitor markers These cavernoma-initiating cells can attract the surrounding wild-type endothelial cells and induce their mesenchymal transition, coinciding with a strong and timedependent increase in the size of the cavernomas. Data indicate that a minimal proportion of Ccm3-null endothelial cells can induce large-sized malformations, as in the human disease[8,9] This concept is in agreement with the fact that Ccm[3] is a tumour suppressor[18,19] and its deletion may be correlated to benign brain tumours[20]
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