Vascular Biology Unit, The FIRC Institute of Molecular Oncology Foundation, Milan, 20139, Italy.
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, 752 37, Sweden.
Nat Commun. 2019 Jun 24;10(1):2761. doi: 10.1038/s41467-019-10707-x.
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.
脑内海绵状血管畸形（CCM）是一种神经血管性家族性或散发性疾病，其特征为毛细血管-静脉海绵状畸形，是由于任何一个 CCM 基因的功能丧失性突变所致。家族性 CCM 遵循类似于肿瘤抑制基因的“双打击”机制，而在散发性海绵状血管畸形中，只有一小部分内皮细胞显示突变的 CCM 基因。我们曾报道，在小鼠模型和人类患者中，病变处的内皮细胞与周围内皮细胞具有不同的特征，因为它们表达间充质/干细胞标志物。在这里，我们显示海绵状血管畸形起源于少数表达间充质/干细胞标志物的 Ccm3 缺失内皮细胞的克隆扩张。这些细胞随后吸引周围的野生型内皮细胞，诱导它们表达间充质/干细胞标志物，并促进海绵状血管畸形的生长。Ccm3 缺失细胞的这些特征使人联想到负责肿瘤生长的肿瘤起始细胞。我们的数据支持 CCM 具有良性肿瘤特征的概念。
