Sartages Miriam, Floridia Ebel, García-Colomer Mar, Iglesias Cristina, Macía Manuel, Peñas Patricia, Couraud Pierre-Olivier, Romero Ignacio A, Weksler Babette, Pombo Celia M, Zalvide Juan
Department of Physiology, Centro Singular de Medicina Molecular e Enfermedades Crónicas (CiMUS), Instituto Sanitario de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15703 Santiago de Compostela, Spain.
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Biomedicines. 2020 Dec 17;8(12):624. doi: 10.3390/biomedicines8120624.
Cerebral cavernous malformations (CCMs) are vascular malformations that can be the result of the deficiency of one of the CCM genes. Their only present treatment is surgical removal, which is not always possible, and an alternative pharmacological strategy to eliminate them is actively sought. We have studied the effect of the lack of one of the CCM genes, CCM3, in endothelial and non-endothelial cells. By comparing protein expression in control and CCM3-silenced cells, we found that the levels of the Epidermal Growth Factor Receptor (EGFR) are higher in CCM3-deficient cells, which adds to the known upregulation of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in these cells. Whereas VEGFR2 is upregulated at the mRNA level, EGFR has a prolonged half-life. Inhibition of EGFR family members in CCM3-deficient cells does not revert the known cellular effects of lack of CCM genes, but it induces significantly more apoptosis in CCM3-deficient cells than in control cells. We propose that the susceptibility to tyrosine kinase inhibitors of CCM3-deficient cells can be harnessed to kill the abnormal cells of these lesions and thus treat CCMs pharmacologically.
脑海绵状血管畸形(CCMs)是一种血管畸形,可能是由于CCM基因之一缺失所致。目前其唯一的治疗方法是手术切除,但这并非总是可行,因此人们正在积极寻找一种替代性的药物治疗策略来消除它们。我们研究了CCM基因之一CCM3缺失在内皮细胞和非内皮细胞中的作用。通过比较对照细胞和CCM3沉默细胞中的蛋白质表达,我们发现CCM3缺陷细胞中表皮生长因子受体(EGFR)的水平更高,这进一步增加了这些细胞中已知的血管内皮生长因子受体2(VEGFR2)的上调。虽然VEGFR2在mRNA水平上上调,但EGFR的半衰期延长。抑制CCM3缺陷细胞中的EGFR家族成员并不能恢复已知的CCM基因缺失所导致的细胞效应,但它在CCM3缺陷细胞中诱导的凋亡比在对照细胞中显著更多。我们提出,可以利用CCM3缺陷细胞对酪氨酸激酶抑制剂的敏感性来杀死这些病变中的异常细胞,从而从药理学上治疗CCMs。