Aldridge SE, Lennard TW, Williams JR, Birch MAVascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone. Br J Cancer 92: 1531-1537

The School of Surgical Sciences, The Medical School, Framlington Place, University of Newcastle upon Tyne, NE2 4HH, UK.
British Journal of Cancer (Impact Factor: 4.84). 05/2005; 92(8):1531-7. DOI: 10.1038/sj.bjc.6602417
Source: PubMed


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.

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    • "A newly discovered molecule downstream of RANKL is extracellular matrix metalloproteinase inducer (EMMPRIN)/CD147, a cell surface glycoprotein that is known to induce MMPs and VEGF [48]. While EMMPRIN is produced normally during tissue remodeling, it increases during tumor progression and metastasis. "
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    ABSTRACT: Breast cancer frequently metastasizes to the skeleton, interrupting the normal bone remodeling process and causing bone degradation. Osteolytic lesions are the end result of osteoclast activity; however, osteoclast differentiation and activation are mediated by osteoblast production of RANKL (receptor activator for NFκB ligand) and several osteoclastogenic cytokines. Osteoblasts themselves are negatively affected by cancer cells as evidenced by an increase in apoptosis and a decrease in proteins required for new bone formation. Thus, bone loss is due to both increased activation of osteoclasts and suppression of osteoblasts. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies.
    Breast cancer research: BCR 12/2010; 12(6):215. DOI:10.1186/bcr2781 · 5.49 Impact Factor
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    • "We found increased VEGF in breast cancer patient with bone metastases, but not in patients with a localised disease, which is consistent with previous studies (Adams et al, 2000; Coskun et al, 2003). Increased VEGF level was also associated with biochemical markers of osteoclastic activity and bone matrix degradation, which is in agreement with a recent study showing high that VEGF stimulates osteoclastic differentiation in vitro (Aldridge et al, 2005). "
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    ABSTRACT: Complex biological pathways including angiogenesis, invasion, osteoclastic activation and bone matrix degradation are involved in the formation of bone metastasis (BM). The aim of our study was to investigate the cross-sectional and longitudinal associations of a panel of 12 serum biochemical markers reflecting biological pathways underlying BM development. In a cross-sectional study, we investigated 29 patients with primary breast carcinoma without BM (BC/BM-), 28 patients with breast carcinoma and BM (BC/BM+) and 15 healthy women. In longitudinal analyses, we investigated 34 patients for whom serum was obtained a two different time points: at the time of primary BC diagnosis and after a median time of 3 years. During this follow-up, 15 patients developed BM, whereas the other 19 remained free of BM. In patients who developed BM, the second samples were obtained before BM was documented by bone scan. The cross-sectional analyses have shown all biochemical markers to be significantly elevated in patients with BM, when compared to the patients without BM and healthy controls, except TGFbeta1 that was significantly decreased. Multivariable analyses showed that only the bone resorption markers TRACP 5b, CTX and ICTP, and the marker of angiogenesis VEGF were independently associated with BM. Those markers correctly distinguished 85% of BC patients with or without BM from normal individuals. Longitudinal analyses showed that patients with primary BC who developed BM during follow-up had higher levels of TRACP5b (+95%, P=0.08) at the time of primary diagnosis, those patients had also a higher increases of ICTP (P=0.006), MMP-7 (P=0.004) and TIMP-1 (P=0.017) during follow-up than patients who did not progress toward bone metastasis. This study provides evidence of increase and interrelationship of circulating markers of angiogenesis, invasion and bone resorption in patients with BC with and without BM. Markers of bone resorption have the highest independent diagnostic value for detecting and potentially predicting BM in breast carcinoma patients.
    British Journal of Cancer 09/2006; 95(4):506-14. DOI:10.1038/sj.bjc.6603285 · 4.84 Impact Factor
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    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).
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