title: Combination of anti-angiogenic therapies reduces osteolysis and tumor burden in experimental breast cancer bone metastasis.
abstract: The clinical efficacy of anti-angiogenic monotherapies in metastatic breast cancer is less than originally anticipated, and it is not clear what the response of bone metastasis to anti-angiogenic therapies is. Here, we examined the impact of neutralizing tumor-derived vascular endothelial growth factor (VEGF) in animal models of subcutaneous tumor growth and bone metastasis formation. Silencing of VEGF expression (Sh-VEGF) in osteotropic human MDA-MB-231/B02 breast cancer cells led to a substantial growth inhibition of subcutaneous Sh-VEGF B02 tumor xenografts, as a result of reduced angiogenesis, when compared to that observed with animals bearing mock-transfected (Sc-VEGF) B02 tumors. However, there was scant evidence that either the silencing of tumor-derived VEGF or the use of a VEGF-neutralizing antibody (bevacizumab) affected B02 breast cancer bone metastasis progression in animals. We also examined the effect of vatalanib (a VEGF receptor tyrosine kinase inhibitor) in this mouse model of bone metastasis. However, vatalanib failed to inhibit bone metastasis caused by B02 breast cancer cells. In sharp contrast, vatalanib in combination with bevacizumab reduced not only bone destruction but also skeletal tumor growth in animals bearing breast cancer bone metastases, when compared with either agent alone. Thus, our study highlights the importance of targeting both the tumor compartment and the host tissue (i.e., skeleton) to efficiently block the development of bone metastasis. We believe this is a crucially important observation as the clinical benefit of anti-angiogenic monotherapies in metastatic breast cancer is relatively modest.
authors.affiliation: INSERM, UMR 1033, F-69372, Lyon, France; University of Lyon, F-69622, Villeurbanne, France; LabEx DEVweCAN, F-69372, Lyon, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Bachelier
authors.forename: Cyrille B
authors.initials: CB
authors.lastname: Confavreux
authors.forename: Olivier
authors.initials: O
authors.lastname: Peyruchaud
authors.forename: Martine
authors.initials: M
authors.lastname: Croset
authors.forename: Delphine
authors.initials: D
authors.lastname: Goehrig
authors.forename: Gabri
authors.initials: G
authors.lastname: van der Pluijm
authors.forename: Philippe
authors.initials: P
authors.lastname: Clézardin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D000068258:Bevacizumab; D001859:Bone Neoplasms / Q000098:blood supply / Q000235:genetics / Q000556:secondary* / Q000628:therapy*; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016867:Immunocompromised Host; D051379:Mice; D008809:Mice, Inbred C3H; D010014:Osteolysis / Q000188:drug therapy / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage; D011247:Pregnancy; D011725:Pyridines / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D010793:Phthalazines; D011725:Pyridines; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C404768:vatalanib; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: VEGF; bevacizumab; bone; metastasis; vatalanib