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Inhibitory effects of antivascular endothelial growth factor strategies in experimental dopamine-resistant
Guillermina María Luque1, Maria Ines Perez-Millán, Ana Maria Ornstein
1Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, Buenos Aires 1428, Argentina.
Abstract:
Prolactin-secreting adenomas are the most frequent type among pituitary tumors, and pharmacological therapy with dopamine agonists remains the mainstay of treatment. But some adenomas are resistant, and a decrease in the number or function of dopamine D2 receptors (D2Rs) has been described in these cases. D2R knockout [Drd2(-/-)] mice have chronic hyperprolactinemia and pituitary hyperplasia and provide an experimental model for dopamine agonist-resistant prolactinomas. We described previously that disruption of D2Rs increases vascular endothelial growth factor (VEGF) expression. We therefore designed two strategies of antiangiogenesis using prolactinomas generated in Drd2(-/-) female mice: direct intra-adenoma mVEGF R1 (Flt-1)/Fc chimera (VEGF-TRAP) injection for 3 weeks [into subcutaneously transplanted pituitaries from Drd2(-/-) mice] and systemic VEGF neutralization with the specific monoclonal antibody G6-31. Both strategies resulted in substantial decrease of prolactin content and lactotrope area, and a reduction in tumor size was observed in in situ prolactinomas. There were significant decreases in vascularity, evaluated by cluster of differentiation molecule 31 vessel staining, and proliferation (proliferating cell nuclear antigen staining) in response to both anti-VEGF treatments. These data demonstrate that the antiangiogenic approach was effective in inhibiting the growth of in situ dopamine-resistant prolactinomas as well as in the transplanted adenomas. No differences in VEGF protein expression were observed after either anti-VEGF treatment, and, although serum VEGF was increased in G6-31-treated mice, pituitary activation of the VEGF receptor 2 signaling pathway was reduced. Our results indicate that, even though the role of angiogenesis in pituitary adenomas is contentious, VEGF might contribute to adequate vascular supply and represent a supplementary therapeutic target in dopamine agonist-resistant prolactinomas.
Insights
Antiangiogenesis therapies targeting vascular endothelial growth factor (VEGF) effectively reduced tumor size and proliferation in dopamine agonist-resistant prolactinomas. This suggests VEGF is a potential therapeutic target for these resistant pituitary tumors.
Area of Science:
- Endocrinology
- Oncology
- Vascular Biology
Background:
- Prolactin-secreting adenomas are common pituitary tumors, typically treated with dopamine agonists.
- Dopamine agonist resistance occurs in some adenomas, linked to reduced dopamine D2 receptor (D2R) function.
- D2R knockout mice model dopamine agonist-resistant prolactinomas and exhibit increased vascular endothelial growth factor (VEGF) expression.
Purpose of the Study:
- To investigate the efficacy of antiangiogenic strategies targeting VEGF in experimental dopamine agonist-resistant prolactinomas.
- To evaluate the impact of VEGF inhibition on tumor growth, vascularity, and proliferation in a preclinical model.
Main Methods:
- Utilized D2R knockout mice with spontaneous prolactinomas.
- Administered two antiangiogenic treatments: intra-adenoma VEGF-TRAP and systemic anti-VEGF monoclonal antibody (G6-31).
- Assessed tumor size, prolactin content, lactotrope area, vascularity (CD31 staining), and proliferation (PCNA staining).
Main Results:
- Both anti-VEGF strategies significantly reduced prolactin content, lactotrope area, and tumor size.
- Vascularity and proliferation were significantly decreased in response to anti-VEGF treatments.
- Pituitary VEGF receptor 2 signaling was reduced, despite no change in overall VEGF protein expression.
Conclusions:
- Antiangiogenic approaches targeting VEGF are effective in inhibiting the growth of dopamine agonist-resistant prolactinomas.
- VEGF plays a role in the vascular supply of these tumors and represents a potential supplementary therapeutic target.
- These findings support further investigation of antiangiogenic therapies for resistant pituitary adenomas.
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