Infantile hemangioma: Therapeutic targets through analysis of molecular mechanism

婴儿血管瘤是婴儿期最常见的肿瘤，通常出现在头部和颈部 在出生后第二周左右，在几周和几个月内迅速生长（增殖期）， 在7-10年内缓慢退化（退化阶段）。大多数血管瘤是单一的，小病灶，但有些 可以破坏正常组织或威胁生命。在组织和内皮细胞的研究中， 我们发现血管瘤中VEGFR 1表达仅为对照内皮细胞中的10- 20 和纸巾。低VEGFR 1水平导致VEGFR 2及其下游的VEGF依赖性激活 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VEGFR 1或VEGF抗体降低了它们的高表达。 VEGFR 2信号传导和增殖活性。我们进一步证明了VEGFR 1的低表达与肿瘤细胞的增殖有关。 血管瘤是由涉及VEGFR 2的NFAT控制复合物的活性降低引起的，VEGFR 2是整合素， 如受体TEM 8和pi整联蛋白。在三个血管瘤患者（九个研究）杂合错义 VEGFR 2或TEM 8中的突变为VEGFR 2/TEM 8/pi的活性降低提供了解释。 整合素复合物未来的研究旨在产生携带TEM 8和VEGFR 2突变的小鼠用于研究 突变对血管生成的影响，并确定其他成分， 含VEGFR 2/TEM 8/pi整联蛋白的复合物。与项目3合作，这些组成部分将 筛选血管瘤中的突变，其中未发现VEGFR 2或TEM 8中的突变。 在内皮细胞凋亡调控途径的初步研究中，我们还计划研究 旨在确定加速临床问题血管瘤退化的策略 肿瘤的与项目2合作，将移植到免疫功能低下的小鼠中， 疾病修饰药物的临床前测试，并测试血管瘤内皮细胞 表型可以通过局部和持续激活 VEGFR2. 相关性（参见说明）： 这些研究预计将导致确定药物的靶点，以有效地治疗快速增长的 婴儿血管瘤，儿童期最常见的肿瘤。这项工作也可能对 成人中涉及异常血管生成的其他疾病。

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.