Article

Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone

The School of Surgical Sciences, The Medical School, Framlington Place, University of Newcastle upon Tyne, NE2 4HH, UK.
British Journal of Cancer (Impact Factor: 4.82). 05/2005; 92(8):1531-7. DOI: 10.1038/sj.bjc.6602417
Source: PubMed

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.

Download full-text

Full-text

Available from: Thomas W J Lennard, Aug 22, 2015
0 Followers
 · 
90 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ľangiogenèse, processus impliqué dans le développement de nouveaux vaisseaux sanguins, joue un rôle primordial à la fois dans la croissance locale et dans le processus métastatique des cancers du sein (1). Le VEGF (Vascular Endothelial Growth Factor) est un des promoteurs les plus puissants de ľangiogenèse, impliqué dans la croissance des cellules endothéliales, leur motilité et la perméabilité des structures vasculaires. La surexpression de VEGF est fréquente dans le cancer du sein, particulièrement dans les formes inflammatoires, et est associée à un pronostic défavorable en comparaison aux tumeurs ne présentant pas de surexpression. La plupart des fonctions du VEGF passent par le récepteur de type II du VEGF (VEGFR2). Les traitements antiangiogéniques ont pour but de priver la tumeur de sa vascularisation et donc de prévenir la croissance tumorale. À la différence des agents cytotoxiques, il n’est pas toujours possible ďobtenir une régression tumorale objective et le but de ces traitements est souvent ďobtenir un arrêt de la croissance de la tumeur. Dans ce cas, les critères de réponse seront différents et il est nécessaire de développer de nouveaux paramètres pouvant prédire ľefficacité du traitement (imagerie fonctionnelle, cellules endothéliales circulantes). Deux approches principales de traitements antiangiogéniques ont été développées pour inhiber la signalisation de ces récepteurs: les traitements par anticorps monoclonaux et les inhibiteurs de récepteurs à tyrosine kinase (2).
  • [Show abstract] [Hide abstract]
    ABSTRACT: Osteoclasts are derived from haematopoietic stem cell precursors of the monocyte/macrophage cell lineage, through interaction with factors that are believed to include M-CSF and RANKL. VEGF is a proangiogenic cytokine that has been shown to promote osteoclast differentiation and survival. In this study, we assessed the role of VEGF and its receptors in osteoclastogenesis, in vitro, by culturing osteoclast precursors in the presence of VEGF, VEGF receptor-specific ligands, and blocking antibodies to VEGF receptors. Activation of VEGFR1 in the presence of RANKL induces osteoclast differentiation. Stimulating the receptors individually induced increased resorption by osteoclasts compared to controls but not to the level observed when stimulating both receptors simultaneously. We have shown that VEGF induces osteoclast differentiation through its action on VEGFR1. The way in which VEGF mediates its effect on mature osteoclast activity, however, may be through its interaction with both receptor subtypes.
    Biochemical and Biophysical Research Communications 10/2005; 335(3):793-8. DOI:10.1016/j.bbrc.2005.07.145 · 2.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Angiogenic factors including endothelin-1 (ET-1) play a key role in the progression of breast metastases to bone. We investigated the impact of ET-1 on the development of bone metastases in an immunocompetent murine skin-fold chamber model. Murine mammary carcinoma 4T1 was injected in a skin-fold chamber implanted on CB6 mice along with bone explants. Furthermore, mice were treated with or without a dual selective antagonist of both ET-1 receptors. The progression of the vascularization within the chamber was monitored over time by intravital microscopy (IVM). The tumor growth and the development of bone metastases were assessed by cytokeratin-19 gene expression and histological studies. Results indicate that this new model associated with IVM allows for the continuous monitoring of the change in vascularization associated with the development of bone metastases. Additionally, treatment with an antagonist of both ET-1 receptors was associated with the presence of significantly less vessels near the tumor mass compared to control mice. These changes were correlated with smaller tumor masses and reduced bone invasion (P < 0.05). Thus, in an immunocompetent murine model of breast carcinoma metastases to bone, our data support the hypothesis that vascularization plays a role in tumor development and progression and that ET-1 specifically modulates the angiogenesis associated with breast metastases to the bone.
    Clinical and Experimental Metastasis 02/2006; 23(1):41-53. DOI:10.1007/s10585-006-9016-z · 3.73 Impact Factor
Show more