Vascular Endothelial Growth Factor, Its Receptor KDR/Flk-1, and Pituitary Tumor Transforming Gene in Pituitary Tumors

Pituitary tumorigenesis is a poorly understood process involving dysregulation of the cell cycle, proliferation, and angiogenesis. The novel securin pituitary tumor transforming gene (PTTG) disrupts cell division and stimulates fibroblast growth factor (FGF)-2-mediated angiogenesis. We investigated...

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Published in:The journal of clinical endocrinology and metabolism 2002-09, Vol.87 (9), p.4238-4244
Main Authors: McCabe, C. J, Boelaert, K, Tannahill, L. A, Heaney, A. P, Stratford, A. L, Khaira, J. S, Hussain, S, Sheppard, M. C, Franklyn, J. A, Gittoes, N. J. L
Format: Article
Language:English
Subjects:
Adenoma - blood supply
Adenoma - genetics
Adenoma - surgery
Amino Acid Substitution
Base Sequence
Biological and medical sciences
DNA Primers
Endocrinopathies
Endothelial Growth Factors - genetics
Gene Expression Regulation, Neoplastic
Humans
Hypothalamus. Hypophysis. Epiphysis (diseases)
Lymphokines - genetics
Medical sciences
Mutagenesis, Site-Directed
Neoplasm Proteins - genetics
Neovascularization, Pathologic - genetics
Non tumoral diseases. Target tissue resistance. Benign neoplasms
Pituitary Gland - metabolism
Pituitary Neoplasms - blood supply
Pituitary Neoplasms - genetics
Pituitary Neoplasms - surgery
Polymerase Chain Reaction
Receptor Protein-Tyrosine Kinases - genetics
Receptors, Growth Factor - genetics
Receptors, Vascular Endothelial Growth Factor
Recombinant Proteins - metabolism
Regression Analysis
RNA, Messenger - genetics
Securin
Trans-Activators - genetics
Transcription, Genetic
Transfection
Tumor Cells, Cultured
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
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Summary:Pituitary tumorigenesis is a poorly understood process involving dysregulation of the cell cycle, proliferation, and angiogenesis. The novel securin pituitary tumor transforming gene (PTTG) disrupts cell division and stimulates fibroblast growth factor (FGF)-2-mediated angiogenesis. We investigated expression of the angiogenic vascular endothelial growth factor (VEGF) and its receptor KDR/Flk-1 in 103 human pituitary tumors, and we assessed functional relationships between these genes in vitro. Nonfunctioning tumors (n = 81) demonstrated markedly raised VEGF mRNA (3.2-fold, P < 0.05) and protein concentrations, compared with normal pituitaries (n = 10). KDR was also highly induced in nonfunctioning tumors (14-fold, P < 0.001, n = 78) as well as in the whole cohort of pituitary tumors, compared with normal pituitary samples (14-fold, P < 0.0001, n = 100). In vitro, PTTG induced VEGF, but not KDR, expression in fetal neuronal NT2 cells (2.7-fold, P < 0.001, n = 8), MCF-7 breast carcinoma cells (1.9-fold, P = 0.03, n = 10), and choriocarcinoma JEG-3 cells (P = 0.0002, n = 8). A mutated PTTG construct that cannot be phosphorylated showed identical VEGF up-regulation (2.9-fold, P < 0.001, n = 8) in NT2 cells, compared with wild-type PTTG, but a further mutated construct with abrogation of the key protein:protein interaction domain of PTTG resulted in a significant reduction in VEGF stimulation, compared with wild-type (0.37-fold reduction, P < 0.001, n = 8). FGF-2 findings mirrored those of VEGF, although antibody depletion of secreted FGF-2 in the cell medium failed to influence VEGF up-regulation by PTTG. Overall, our findings implicate altered VEGF and KDR signaling in pituitary tumorigenesis, and we propose that PTTG stimulation of FGF-2 and VEGF expression in the presence of up-regulated growth factor receptors may account for angiogenic growth and progression of human pituitary tumors.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2002-020309