Infantile hemangioma: Therapeutic targets through analysis of molecular mechanism

婴幼儿血管瘤是婴儿期最常见的肿瘤，多见于头颈部。 在生命的第二周左右，在几周和几个月内迅速生长(增殖期)，以及 在7-10年(消退期)内缓慢退化。大多数血管瘤是单一的小病变，但也有一些 会破坏正常组织或威胁生命。在增殖期组织和内皮细胞的研究中 我们发现血管瘤中VEGFR1的表达仅为对照内皮细胞的10-20% 还有纸巾。低水平的VEGFR1导致VEGFR2及其下游的血管内皮生长因子依赖的激活 信号靶点，包括已知在血管瘤组织中异常表达的基因。 向血管瘤内皮细胞添加可溶性VEGFR1或VEGF抗体可降低其高表达 VEGFR2信号转导和增殖活性。我们进一步证明，血管内皮生长因子受体1的低表达 血管瘤是由涉及VEGFR2的NFAT控制复合体活性降低引起的，整合素- 如受体TEM8和pi整合素。3例血管瘤患者(9例研究中)杂合子错义 VEGFR2或TEM8的突变为VEGFR2/TEM8/pi活性降低提供了解释 整合素复合体。未来的研究旨在产生携带TEM8和VEGFR2突变的小鼠进行研究 突变对血管生成的影响和对血管生成的额外成分的鉴定 VEGFR2/TEM8/pi整合素复合体。在与项目3的合作中，这些组件将 对尚未发现VEGFR2或TEM8突变的血管瘤进行突变筛查。基座 在对调控内皮细胞凋亡的途径的初步研究中，我们还计划进行 消退性血管瘤旨在确定加速临床有问题的血管瘤消退的策略 肿瘤。在与Project 2的合作下，移植到免疫低下的小鼠将用于 疾病修饰药物的临床前试验，并检验血管瘤内皮细胞 通过局部和持续的激活，可以在携带危险因子突变的细胞中诱导表型 血管内皮生长因子2。 相关性(请参阅说明)： 这些研究有望确定有效治疗快速增长的药物的靶点。 婴幼儿血管瘤，儿童最常见的肿瘤。这项工作也可能对 其他成人疾病，涉及异常血管生成。

Infantile hemangiomas are the most common tumors in infancy, typically appearing on head and neck around the second week of life, growing rapidly (proliferating phase) over a few weeks and months, and slowly regressing over 7-10 years (involuting phase). Most hemangiomas are single, small lesions, but some can destroy normal tissue or threaten life. In studies of tissues and endothelial cells from proliferating-phase hemangiomas we have found expression of VEGFR1 to be only 10-20% of that in control endothelial cells and tissues. Low VEGFR1 levels result in VEGF-dependent activation of VEGFR2 and its downstream signaling targets, including genes already known to be abnormally expressed in hemangioma tissue. Addition of soluble VEGFR1 or VEGF antibodies to hemangioma endothelial cells reduces their high VEGFR2 signaling and proliferative activities. We have further shown that low expression of VEGFR1 in hemangioma is caused by reduced activity of an NFAT-controlling complex involving VEGFR2, the integrin- like receptor TEM8 and pi integrin. In three hemangioma patients (of nine studied) heterozygous missense mutations in VEGFR2 or TEM8 provide an explanation for the reduced activity of the VEGFR2/TEM8/pi integrin complex. Future studies aim at generating mice carrying TEM8 and VEGFR2 mutations for studies of the effects of the mutations on angiogenesis and identification of additional components of the VEGFR2/TEM8/pi integrin -containing complex. In collaboration with Project 3 such components will be screened for mutations in hemangiomas where mutations in VEGFR2 or TEM8 have not been found. Based on preliminary studies of pathways that regulate apoptosis in endothelial cells, we also plan studies of involuting hemangiomas aimed at identifying strategies to accelerate involution in clinically problematic tumors. In collaboration with Project 2 transplantation into immunocompromised mice will be used for preclinical testing of disease-modifying drugs and to test the hypothesis that the hemangioma endothelial phenotype can be induced in cells carrying risk factor mutations by localized and sustained activation of VEGFR2. RELEVANCE (See instructions): These studies are anticipated to lead to identification of targets for drugs to effectively treat rapidly growing infantile hemangiomas, the most common tumors of childhood. The work is also likely to have impact on other diseases in adults involving abnormal angiogenesis.