Abstract
As for any solid tumour, pituitary adenoma expansion is dependent on neovascularization through angiogenesis. In this process, vascular endothelial growth factor (VEGF) and its receptors VEGFR-1, VEGFR-2 and neuropilin-1 (NRP-1) may play an outstanding role. The intention of this work was to study the expression/localization and possible function of VEGF receptors in pituitary adenomas. VEGF receptor mRNA and protein expression was studied by in situ hybridization, immunohistochemistry and RT-PCR in 6 normal human pituitaries, 39 human pituitary adenomas and 4 rodent pituitary adenoma cell lines. VEGFR-1 expressing somatotroph MtT-S cells were used as a model to study the role of VEGF on cell proliferation and to elucidate the underlying mechanism of action. In normal pituitaries, VEGFR-1 was detected in endocrine cells, whereas VEGFR-2 and NRP-1 were exclusively expressed in endothelial cells. In pituitary tumours, a heterogeneous VEGFR expression pattern was observed by IHC. VEGFR-1, VEGFR-2 and NRP-1 were detected in 24, 18 and 17 adenomas respectively. In the adenomas, VEGFR-1 was expressed in epithelial tumour cells and VEGFR-2/NRP-1 in vessel endothelial cells. Functional studies in VEGFR-1-positive MtT-S cells showed that the ligands of VEGFR-1 significantly stimulated cell proliferation. This effect was mediated through the phosphatidylinositol-3-kinase-signalling pathway and involves induction of cyclin D1 and Bcl-2. Based on our results, we speculate that the ligands of VEGF receptors, such as VEGF-A and placenta growth factor, not only play a role in angiogenesis in pituitary adenomas, but also affect the growth of pituitary tumour cells through VEGFR-1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoma / chemistry*
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Adenoma / metabolism
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Adenoma / pathology
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Adult
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Aged
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Animals
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Antibodies, Monoclonal / pharmacology
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Blotting, Western / methods
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chromones / pharmacology
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Endothelial Cells / chemistry
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Female
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Humans
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Immunohistochemistry / methods
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In Situ Hybridization / methods
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Ligands
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Male
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Middle Aged
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Morpholines / pharmacology
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Neuropilin-1 / genetics
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Phosphoinositide-3 Kinase Inhibitors
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Pituitary Gland / chemistry*
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Pituitary Gland / metabolism
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Pituitary Neoplasms / chemistry*
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Pituitary Neoplasms / metabolism
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Pituitary Neoplasms / pathology
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Rats
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Receptors, Vascular Endothelial Growth Factor / analysis*
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Receptors, Vascular Endothelial Growth Factor / immunology
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Receptors, Vascular Endothelial Growth Factor / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Somatotrophs / cytology
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Somatotrophs / drug effects
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Stimulation, Chemical
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Vascular Endothelial Growth Factor A / analysis
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Vascular Endothelial Growth Factor A / metabolism*
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Vascular Endothelial Growth Factor A / pharmacology
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Vascular Endothelial Growth Factor Receptor-1 / analysis
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Vascular Endothelial Growth Factor Receptor-1 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / analysis
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Vascular Endothelial Growth Factor Receptor-2 / genetics
Substances
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Antibodies, Monoclonal
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Chromones
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Ligands
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Neuropilin-1
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Receptors, Vascular Endothelial Growth Factor
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factor Receptor-2