Inhibitory Effects of Antivascular Endothelial Growth factor Strategies in Experimental Dopamine-Resistant Prolactinomas

GUILLERMINA MARIA LUQUE, MARIA INÉS PEREZ- MILLÁN, ANA MARIA ORNSTEIN, CAROLINA CRISTINA AND DAMASIA BECÚ- VILLALOBOS.

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Año: 2011 vol. 337 p. 1 - 9

0022-3565

Prolactin-secreting adenomas are the most frequent typeamong pituitary tumors, and pharmacological therapy with dopamineagonists remains the mainstay of treatment. But someadenomas are resistant, and a decrease in the number orfunction of dopamine D2 receptors (D2Rs) has been describedin these cases. D2R knockout [Drd2(
/
)] mice have chronichyperprolactinemia and pituitary hyperplasia and provide anexperimental model for dopamine agonist-resistant prolactinomas.We described previously that disruption of D2Rs increasesvascular endothelial growth factor (VEGF) expression.We therefore designed two strategies of antiangiogenesis usingprolactinomas generated in Drd2(
/
) female mice: direct intra-adenoma VEGF-TRAP injection for 3 weeks [into subcutaneouslytransplanted pituitaries from Drd2(
/
) mice] and systemicVEGF neutralization with the specific monoclonalantibody G6-31. Both strategies resulted in substantial decreaseof prolactin content and lactotrope area, and a reductionin tumor size was observed in in situ prolactinomas. There weresignificant decreases in vascularity, evaluated by cluster ofdifferentiation molecule 31 vessel staining, and proliferation(proliferating cell nuclear antigen staining) in response to bothanti-VEGF treatments. These data demonstrate that the antiangiogenicapproach was effective in inhibiting the growth of insitu dopamine-resistant prolactinomas as well as in the transplantedadenomas. No differences in VEGF protein expressionwere observed after either anti-VEGF treatment, and, althoughserum VEGF was increased in G6-31-treated mice, pituitaryactivation of the VEGF receptor 2 signaling pathway was reduced.Our results indicate that, even though the role of angiogenesisin pituitary adenomas is contentious, VEGF mightcontribute to adequate vascular supply and represent a supplementarytherapeutic target in dopamine agonist-resistantprolactinomas.