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.
OBJECTIVE
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.


METHODS
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.
Korsisaari
Nina
N
Genentech, Inc., South San Francisco, California 94080, USA.
Ross
Jed
J
Wu
Xiumin
X
Kowanetz
Marcin
M
Pal
Navneet
N
Hall
Linda
L
Eastham-Anderson
Jeffrey
J
Forrest
William F
WF
Van Bruggen
Nicholas
N
Peale
Franklin V
FV
Ferrara
Napoleone
N
D000236:Adenoma / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D018761:Multiple Endocrine Neoplasia Type 1 / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D010911:Pituitary Neoplasms / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D011388:Prolactin / Q000097:blood*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000187:drug effects
D000911:Antibodies, Monoclonal; D042461:Vascular Endothelial Growth Factor A; D011388:Prolactin