Somatic PIK3CA mutations as a driver of sporadic venous malformations.
Somatic PIK3CA mutations as a driver of sporadic venous malformations.
复制标题
DOI：
10.1126/scitranslmed.aaf1164
复制
发表时间：
2016-03-30
影响因子：
17.1
通讯作者：
Baselga J
中科院分区：
文献类型：
--
作者：
Castel P;Carmona FJ;Grego-Bessa J;Berger MF;Viale A;Anderson KV;Bague S;Scaltriti M;Antonescu CR;Baselga E;Baselga J
静脉畸形是以血管通道增大和扭曲为特征的血管畸形。VM随着时间的推移而增长，并因毁容、出血和疼痛而导致相当大的发病率，这在缺乏有效治疗的情况下是一个临床挑战(Nguyen等人，2014；Uebelhoer等人，2012)。体细胞突变可能是这些损害的驱动因素，正如在一定比例的VM中发现TEK突变所表明的那样(Limaye等人，2009年)。我们报告说，激活PIK3CA突变会在小鼠中引起散发性VM，这与人类疾病的组织学非常相似。此外，我们在大约30%缺乏TEK改变的人类VM中发现了PIK3CA和PI3K(磷脂酰肌醇3-激酶)/AKT途径的相关基因的突变。PIK3CA突变促进内皮细胞的下游信号转导和增殖，损害胚胎发育过程中正常的血管生成。我们使用PI3Kα的药理抑制剂成功地治疗了小鼠模型中的VM，无论是全身给药还是局部给药。这项研究阐明了部分VM的病因，并提出了一种治疗该疾病的方法。
Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyen et al., 2014; Uebelhoer et al., 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification of TEK mutations in a proportion of VM (Limaye et al., 2009). We report that activating PIK3CA mutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations in PIK3CA and related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lack TEK alterations. PIK3CA mutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kα administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease.