Journal
ANNALS OF ONCOLOGY
Volume 23, Issue 3, Pages 597-+Publisher
OXFORD UNIV PRESS
DOI: 10.1093/annonc/mdr159
Keywords
breast cancer; mesenchymal stem cells; metastases; tumor microenvironment; zoledronic acid
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Funding
- Associazione Italiana per la Ricerca sul Cancro
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Background: Zoledronic acid (ZA) reduces locoregional and distant metastases in estrogen receptor (ER)-positive breast cancer patients. Since ZA rapidly concentrates in the bone following i.v. administration, we hypothesized that this phenomenon involves the mechanism of action of ZA in bone tissue. Materials and methods: Migration assays were carried out in fibronectin-coated Boyden chambers. Activation of signaling proteins was analyzed with a phosphoprotein array. Chemokines and growth factors were measured by immunoassays and real-time PCR. Results: ZA significantly reduced in bone marrow-derived mesenchymal stem cells (MSCs) the activation of AKT and mitogen-activated protein kinase and their ability to migrate. Conditioned medium (CM) from ZA-treated MSCs showed a reduced capacity to promote the migration of ER-positive MCF-7 breast cancer cells as compared with CM from untreated MSCs. The levels of the chemokine (C-C motif) ligand 5 (CCL5, also known as RANTES - Regulated upon Activation, Normal T-cell Expressed, and Secreted) and interleukin (IL)-6 were significantly reduced in MSC-CM following treatment with ZA. Anti-RANTES and anti-IL-6 antibodies almost completely abolished the migration of MCF-7 cells induced by MSC-CM. Recombinant RANTES and IL-6 significantly induced MCF-7 cell migration and their combination showed a cooperative effect. Similar results were observed in different breast cancer cell lines. Conclusion: ZA might exert its antitumor activity by inhibiting MSC migration and blocking MSCs' secretion of factors involved in breast cancer progression.
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