title: Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone.
abstract: Vascular endothelial growth factor (VEGF) is a proangiogenic cytokine that is expressed highly in many solid tumours often correlating with a poor prognosis. In this study, we investigated the expression of VEGF and its receptors in bone metastases from primary human breast tumours and further characterised its effects on osteoclasts in vitro. Breast cancer metastases to bone were immunohistochemically stained for VEGF, its receptors VEGFR1 and 2 (vascular endothelial growth factor receptor 1 and 2), demonstrating that breast cancer metastases express VEGF strongly and that surrounding osteoclasts express both VEGFR1 and VEGFR2. RAW 264.7 cells (mouse monocyte cell line) and human peripheral blood mononuclear cells (PBMCs) were cultured with VEGF, RANKL and M-CSF. VEGF and RANKL together induced differentiation of multinucleated, tartrate-resistant acid phophatase (TRAP)-positive cells in similar numbers to M-CSF and RANKL. The PBMCs were also able to significantly stimulate resorption of mineralised matrix after treatment with M-CSF with RANKL and VEGF with RANKL. We have shown that VEGF in the presence of RANKL supports PBMC differentiation into osteoclast-like cells, able to resorb substrate. Vascular endothelial growth factor may therefore play a role in physiological bone resorption and in pathological situations. Consequently, VEGF signalling may be a therapeutic target for osteoclast inhibition in conditions such as tumour osteolysis.
authors.affiliation: The School of Surgical Sciences, The Medical School, Framlington Place, University of Newcastle upon Tyne, NE2 4HH, UK. stephen.aldridge@ncl.ac.uk
authors.forename: S E
authors.initials: SE
authors.lastname: Aldridge
authors.forename: T W J
authors.initials: TW
authors.lastname: Lennard
authors.forename: J R
authors.initials: JR
authors.lastname: Williams
authors.forename: M A
authors.initials: MA
authors.lastname: Birch
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D002352:Carrier Proteins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000494:pharmacology; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010014:Osteolysis / Q000378:metabolism*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor