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.
Highlights
Angiogenesis, the formation of new blood vessels from pre-existing ones, is known to be a fundamental process in the expansion of solid tumours (Carmeliet 2003, Ferrara 2004) and is essential for pituitary adenoma progression (Gorczyca & Hardy 1988, Turner et al 2000, 2003, Vidal et al 2001)
vascular endothelial growth factor (VEGF)-A binds to different tyrosine kinase receptors, such as VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR), which are mainly expressed in the endothelial cells of blood vessels (Ferrara 2004, Tammela et al 2005)
These cells express neuropilin-1 (NRP-1), a VEGFR-2 co-receptor lacking intracellular signalling tyrosine kinase domain and enhancing only VEGF-A binding to VEGFR-2 (Soker et al 1998)
Summary
Angiogenesis, the formation of new blood vessels from pre-existing ones, is known to be a fundamental process in the expansion of solid tumours (Carmeliet 2003, Ferrara 2004) and is essential for pituitary adenoma progression (Gorczyca & Hardy 1988, Turner et al 2000, 2003, Vidal et al 2001). Sprouting of vessels into an expanding tumour is a complex process involving endothelial cell proliferation, vascular tube formation as well as tumour matrix degradation and remodelling during vessel invasion (Carmeliet 2003, Ferrara 2004). VEGF-A binds to different tyrosine kinase receptors, such as VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR), which are mainly expressed in the endothelial cells of blood vessels (Ferrara 2004, Tammela et al 2005). These cells express neuropilin-1 (NRP-1), a VEGFR-2 co-receptor lacking intracellular signalling tyrosine kinase domain and enhancing only VEGF-A binding to VEGFR-2 (Soker et al 1998). Mitogenesis, chemotaxis and changes in endothelial cell morphology are mainly mediated through VEGFR-2
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