Abstract
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. 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. 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. These results suggest that VEGF-A blockade may represent a nonsurgical treatment for benign tumors of the endocrine system.
Highlights
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
To investigate whether anti – vascular endothelial growth factor (VEGF)-A therapy would be effective in inhibiting the growth of pituitary adenomas, 125 eleven- to thirteen-month-old female Men1+/mice were subjected to magnetic resonance imaging to identify mice with pituitary tumors
Given that all pituitary adenomas examined from Men1+/- mice treated with control IgG or monoclonal antibody (mAb) G6-31 were positive for prolactin by immunohistochemical analysis, we investigated whether serum PRL levels were elevated in Men1+/- pituitary adenoma – bearing mice
Summary
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. 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 MEN1patients. A patient is classified with MEN type 1 (MEN1) when a combined occurrence of tumors in the parathyroid glands, the pancreatic islet cells, and the anterior pituitary is identified [14]. Mutations in MEN1 gene were discovered to underlie the disorder [15], which commonly result in a truncation or absence of the protein menin None of the protein interactions identified far, provide an explanation to the tumorigenicity in MEN1
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