title: Localization of vascular endothelial growth factor (VEGF) receptors in normal and adenomatous pituitaries: detection of a non-endothelial function of VEGF in pituitary tumours.
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.
authors.affiliation: Max-Planck-Institute of Psychiatry, Neuroendocrinology Group, Kraepelinstr. 10, D-80804 Munich, Germany. onofri@mpipsykl.mpg.de
authors.forename: Chiara
authors.initials: C
authors.lastname: Onofri
authors.forename: Marily
authors.initials: M
authors.lastname: Theodoropoulou
authors.forename: Marco
authors.initials: M
authors.lastname: Losa
authors.forename: Eberhard
authors.initials: E
authors.lastname: Uhl
authors.forename: Manfred
authors.initials: M
authors.lastname: Lange
authors.forename: Eduardo
authors.initials: E
authors.lastname: Arzt
authors.forename: Günter K
authors.initials: GK
authors.lastname: Stalla
authors.forename: Ulrich
authors.initials: U
authors.lastname: Renner
mesh_terms: D000236:Adenoma / Q000737:chemistry* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D042783:Endothelial Cells / Q000737:chemistry; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D039942:Neuropilin-1 / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010902:Pituitary Gland / Q000737:chemistry* / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000737:chemistry* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D040262:Receptors, Vascular Endothelial Growth Factor / Q000032:analysis* / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D052683:Somatotrophs / Q000166:cytology / Q000187:drug effects; D013268:Stimulation, Chemical; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000032:analysis / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D002867:Chromones; D008024:Ligands; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2