Inhibitory effects of antivascular endothelial growth factor strategies in experimental dopamine-resistant prolactinomas
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...
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todo:paper_00223565_v337_n3_p766_Luque2023-10-03T14:31:57Z Inhibitory effects of antivascular endothelial growth factor strategies in experimental dopamine-resistant prolactinomas Luque, G.M. Perez-Millán, M.I. Ornstein, A.M. Cristina, C. Becu-Villalobos, D. aflibercept dopamine dopamine 2 receptor monoclonal antibody monoclonal antibody G6-31 prolactin unclassified drug vasculotropin vasculotropin receptor 2 animal experiment animal model animal tissue antiangiogenic activity article cancer inhibition cancer transplantation controlled study female mouse nonhuman priority journal prolactinoma protein blood level protein expression signal transduction tumor vascularization Angiogenesis Inhibitors Animals Antibodies, Monoclonal Cell Proliferation Dopamine Female Hyperplasia Mice Mice, Inbred C57BL Mice, Knockout Microvessels Neovascularization, Pathologic Pituitary Gland Pituitary Neoplasms Prolactin Prolactinoma Receptors, Dopamine D2 Recombinant Fusion Proteins Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor Receptor-1 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. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00223565_v337_n3_p766_Luque |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
aflibercept dopamine dopamine 2 receptor monoclonal antibody monoclonal antibody G6-31 prolactin unclassified drug vasculotropin vasculotropin receptor 2 animal experiment animal model animal tissue antiangiogenic activity article cancer inhibition cancer transplantation controlled study female mouse nonhuman priority journal prolactinoma protein blood level protein expression signal transduction tumor vascularization Angiogenesis Inhibitors Animals Antibodies, Monoclonal Cell Proliferation Dopamine Female Hyperplasia Mice Mice, Inbred C57BL Mice, Knockout Microvessels Neovascularization, Pathologic Pituitary Gland Pituitary Neoplasms Prolactin Prolactinoma Receptors, Dopamine D2 Recombinant Fusion Proteins Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor Receptor-1 |
| spellingShingle |
aflibercept dopamine dopamine 2 receptor monoclonal antibody monoclonal antibody G6-31 prolactin unclassified drug vasculotropin vasculotropin receptor 2 animal experiment animal model animal tissue antiangiogenic activity article cancer inhibition cancer transplantation controlled study female mouse nonhuman priority journal prolactinoma protein blood level protein expression signal transduction tumor vascularization Angiogenesis Inhibitors Animals Antibodies, Monoclonal Cell Proliferation Dopamine Female Hyperplasia Mice Mice, Inbred C57BL Mice, Knockout Microvessels Neovascularization, Pathologic Pituitary Gland Pituitary Neoplasms Prolactin Prolactinoma Receptors, Dopamine D2 Recombinant Fusion Proteins Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor Receptor-1 Luque, G.M. Perez-Millán, M.I. Ornstein, A.M. Cristina, C. Becu-Villalobos, D. Inhibitory effects of antivascular endothelial growth factor strategies in experimental dopamine-resistant prolactinomas |
| topic_facet |
aflibercept dopamine dopamine 2 receptor monoclonal antibody monoclonal antibody G6-31 prolactin unclassified drug vasculotropin vasculotropin receptor 2 animal experiment animal model animal tissue antiangiogenic activity article cancer inhibition cancer transplantation controlled study female mouse nonhuman priority journal prolactinoma protein blood level protein expression signal transduction tumor vascularization Angiogenesis Inhibitors Animals Antibodies, Monoclonal Cell Proliferation Dopamine Female Hyperplasia Mice Mice, Inbred C57BL Mice, Knockout Microvessels Neovascularization, Pathologic Pituitary Gland Pituitary Neoplasms Prolactin Prolactinoma Receptors, Dopamine D2 Recombinant Fusion Proteins Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor Receptor-1 |
| description |
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. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics. |
| format |
JOUR |
| author |
Luque, G.M. Perez-Millán, M.I. Ornstein, A.M. Cristina, C. Becu-Villalobos, D. |
| author_facet |
Luque, G.M. Perez-Millán, M.I. Ornstein, A.M. Cristina, C. Becu-Villalobos, D. |
| author_sort |
Luque, G.M. |
| title |
Inhibitory effects of antivascular endothelial growth factor strategies in experimental dopamine-resistant prolactinomas |
| title_short |
Inhibitory effects of antivascular endothelial growth factor strategies in experimental dopamine-resistant prolactinomas |
| title_full |
Inhibitory effects of antivascular endothelial growth factor strategies in experimental dopamine-resistant prolactinomas |
| title_fullStr |
Inhibitory effects of antivascular endothelial growth factor strategies in experimental dopamine-resistant prolactinomas |
| title_full_unstemmed |
Inhibitory effects of antivascular endothelial growth factor strategies in experimental dopamine-resistant prolactinomas |
| title_sort |
inhibitory effects of antivascular endothelial growth factor strategies in experimental dopamine-resistant prolactinomas |
| url |
http://hdl.handle.net/20.500.12110/paper_00223565_v337_n3_p766_Luque |
| work_keys_str_mv |
AT luquegm inhibitoryeffectsofantivascularendothelialgrowthfactorstrategiesinexperimentaldopamineresistantprolactinomas AT perezmillanmi inhibitoryeffectsofantivascularendothelialgrowthfactorstrategiesinexperimentaldopamineresistantprolactinomas AT ornsteinam inhibitoryeffectsofantivascularendothelialgrowthfactorstrategiesinexperimentaldopamineresistantprolactinomas AT cristinac inhibitoryeffectsofantivascularendothelialgrowthfactorstrategiesinexperimentaldopamineresistantprolactinomas AT becuvillalobosd inhibitoryeffectsofantivascularendothelialgrowthfactorstrategiesinexperimentaldopamineresistantprolactinomas |
| _version_ |
1807321912994430976 |