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Combination of anti‐angiogenic therapies reduces osteolysis and tumor burden in experimental breast cancer bone metastasis
Author(s) -
Bachelier Richard,
Confavreux Cyrille B.,
Peyruchaud Olivier,
Croset Martine,
Goehrig Delphine,
Pluijm Gabri,
Clézardin Philippe
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28787
Subject(s) - medicine , metastasis , bone metastasis , breast cancer , angiogenesis , bevacizumab , cancer , osteolysis , vascular endothelial growth factor , metastatic breast cancer , cancer research , oncology , chemotherapy , surgery , vegf receptors
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.