title: Zoledronic acid blocks the interaction between mesenchymal stem cells and breast cancer cells: implications for adjuvant therapy of breast cancer.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  ZA might exert its antitumor activity by inhibiting MSC migration and blocking MSCs' secretion of factors involved in breast cancer progression.
authors.affiliation: Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori - "Fondazione Pascale", Naples, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Gallo
authors.affiliation: Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori - "Fondazione Pascale", Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori - "Fondazione Pascale", Naples, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Lamura
authors.affiliation: Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori - "Fondazione Pascale", Naples, Italy. Electronic address: nicnorm@yahoo.com.
authors.forename: N
authors.initials: N
authors.lastname: Normanno
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D017024:Chemotherapy, Adjuvant / Q000379:methods; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007118:Immunoassay; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid