Blocking vascular endothelial growth factor-A inhibits the growth of pituitary adenomas and lowers serum prolactin level in a mouse model of multiple endocrine neoplasia type 1
Blocking vascular endothelial growth factor-A inhibits the growth of pituitary adenomas and lowers serum prolactin level in a mouse model of multiple endocrine neoplasia type 1
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DOI：
10.1158/1078-0432.ccr-07-1552
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发表时间：
2008-01-01
影响因子：
11.5
通讯作者：
Ferrara, Napoleone
中科院分区：
文献类型：
--
作者：
Korsisaari, Nina;Ross, Jed;Ferrara, Napoleone
目的：多发性内分泌瘤1型（MEN 1）在临床上定义为多种肿瘤的联合发生，通常是甲状旁腺、胰岛细胞和垂体前叶。Men 1基因杂合缺失的小鼠模型重现了MEN 1的肿瘤发生。我们希望确定血管内皮生长因子（VEGF）-A在MEN 1相关肿瘤的血管形成和生长中的作用，重点是垂体腺瘤。实验设计：为了研究Men 1（+/-）小鼠中的肿瘤生长是否由VEGF-A依赖性血管形成介导，我们用抗VEGF-A单克隆抗体（mAb）G6-31进行了单一疗法。我们通过磁共振成像评估肿瘤生长，并评估组织切片中的血管密度。我们还测量了激素水平在serum.Results：在治疗与单克隆抗体G6-31，垂体腺瘤生长的显着抑制被观察到，导致增加的平均无肿瘤倍增生存与对照抗体治疗的小鼠相比。同样，s.c.抗VEGF-A单克隆抗体可有效抑制垂体腺瘤移植瘤。mAb G6-31治疗降低了血清催乳素，但对照抗体没有降低，这可能为治疗MEN 1患者的激素过量提供了一种新的治疗方法。此外，血管密度在胰岛肿瘤显着降低了treatment.Conclusions：这些结果表明，VEGF-A封锁可能代表一种非手术治疗良性肿瘤的内分泌系统。
Purpose: Multiple endocrine neoplasia type 1 (MEN1) is defined clinically by the combined occurrence of multiple tumors, typically of the parathyroid glands, pancreatic islet cells, and anterior pituitary gland. A mouse model with a heterozygous deletion of the Men1 gene recapitulates the tumorigenesis of MEN1. We wished to determine the role of vascular endothelial growth factor (VEGF)-A in the vascularization and growth of MEN1-associated tumors, with an emphasis on pituitary adenomas.Experimental Design: To investigate whether tumor growth in Men1(+/-) mice is mediated by VEGF-A dependent angiogenesis, we carried out a monotherapy with the anti - VEGF-A monoclonal antibody (mAb) G6-31. We evaluated tumor growth by magnetic resonance imaging and assessed vascular density in tissue sections. We also measured hormone levels in the serum.Results: During the treatment with mAb G6-31, a significant inhibition of the pituitary adenoma growth was observed, leading to an increased mean tumor doubling-free survival compared with mice treated with a control antibody. Similarly, the growth of s.c. pituitary adenoma transplants was effectively inhibited by administration of anti - VEGF-A mAb. Serum prolactin was lowered by mAb G6-31 treatment but not by control antibody, potentially providing a new therapeutic approach for treating the hormonal excess in MEN1 patients. Additionally, the vascular density in pancreatic islet tumors was significantly reduced by the treatment.Conclusions: These results suggest that VEGF-A blockade may represent a nonsurgical treatment for benign tumors of the endocrine system.