Abstract
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.
Highlights
Cerebral cavernous malformations (CCMs, OMIM#116860) are vascular malformations with a high prevalence of 1 in 200–250 individuals
The only protein that had a double intensity on shCCM3 cells was Epidermal Growth Factor Receptor (EGFR), whereas several beta-integrins were close to that difference (Figure 1c,d)
We show in this paper that CCM3 deficiency induces an overexpression of the EGF receptor, and a susceptibility of CCM3-deficient cells to inhibition of the EGFR family of receptors
Summary
Cerebral cavernous malformations (CCMs, OMIM#116860) are vascular malformations with a high prevalence of 1 in 200–250 individuals. Biomedicines 2020, 8, 624 has altered cell-to-cell junctions, which causes leakiness [4] These abnormal endothelial features have lent support to the idea that CCMs arise from an abnormal endothelial behavior, which has been confirmed by recent studies [3]. Both sporadic and familial forms of CCMs have been described. There have been three CCM genes identified: CCM1 (KRIT1), CCM2 (MGC4607, OSM, Malcavernin), and CCM3 (PDCD10, TFAR15) [5,6,7] Mutations in these genes are inherited in heterozygosis, and cavernomas are formed when they are completely inactivated in an endothelial cell because of loss of the non-mutated allele [8,9,10]. We still do not fully understand the behavior of a CCM cell and how a cavernoma develops and especially how it could be limited or, ideally, deleted
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