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

Clin Cancer Res. 2008 Jan 1;14(1):249-58. doi: 10.1158/1078-0432.CCR-07-1552.


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.

MeSH terms

  • Adenoma / blood
  • Adenoma / metabolism*
  • Adenoma / pathology
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Disease Models, Animal
  • Immunohistochemistry
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Mutant Strains
  • Mice, Nude
  • Multiple Endocrine Neoplasia Type 1 / blood
  • Multiple Endocrine Neoplasia Type 1 / metabolism
  • Multiple Endocrine Neoplasia Type 1 / pathology*
  • Neovascularization, Pathologic
  • Pituitary Neoplasms / blood
  • Pituitary Neoplasms / metabolism
  • Pituitary Neoplasms / pathology*
  • Prolactin / blood*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / drug effects


  • Antibodies, Monoclonal
  • Vascular Endothelial Growth Factor A
  • Prolactin