title: Zoledronic acid inhibits macrophage/microglia-assisted breast cancer cell invasion.
abstract: The bisphosphonate zoledronic acid (ZA) significantly reduces complications of bone metastasis by inhibiting resident macrophages, the osteoclasts. Recent clinical trials indicate additional anti-metastatic effects of ZA outside the bone. However, which step of metastasis is influenced and whether thisis due to directtoxicity on cancer cells or inhibition of the tumor promoting microenvironment, is unknown. In particular, tumor-associated and resident macrophages support each step of organ metastasis and could be a crucial target of ZA. Thus, we comparatively investigate the ZA effects on: i) different types of macrophages, ii) on breast cancer cells but also iii) on macrophage-induced invasion. We demonstrate that ZA concentrations reflecting the plasma level affected viability of human macrophages, murine bone marrow-derived macrophages as well as their resident brain equivalents, the microglia, while it did not influence the tested cancer cells. However, the effects on the macrophages subsequently reduced the macrophage/microglia-induced invasiveness of the cancer cells. In line with this, manipulation of microglia by ZA in organotypic brain slice cocultures reduced the tissue invasion by carcinoma cells. The characterization of human macrophages after ZA treatment revealed a phenotype/response shift, in particular after external stimulation. In conclusion, we show that therapeutic concentrations of ZA affect all types of macrophages but not the cancer cells. Thus, anti-metastatic effects of ZA are predominantly caused by modulating the microenvironment. Most importantly, our findings demonstrate that ZA reduced microglia-assisted invasion of cancer cells to the brain tissue, indicating a potential therapeutic role in the prevention of cerebral metastasis.
authors.affiliation: Department of Hematology/Oncology, University Medical Center, 37099 Göttingen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Rietkötter
authors.forename: Kerstin
authors.initials: K
authors.lastname: Menck
authors.forename: Annalen
authors.initials: A
authors.lastname: Bleckmann
authors.forename: Katja
authors.initials: K
authors.lastname: Farhat
authors.forename: Meike
authors.initials: M
authors.lastname: Schaffrinski
authors.forename: Matthias
authors.initials: M
authors.lastname: Schulz
authors.forename: Uwe-Karsten
authors.initials: UK
authors.lastname: Hanisch
authors.forename: Claudia
authors.initials: C
authors.lastname: Binder
authors.forename: Tobias
authors.initials: T
authors.lastname: Pukrop
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D061986:MCF-7 Cells; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000473:pathology*; D059016:Tumor Microenvironment / Q000187:drug effects; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D020782:Matrix Metalloproteinases
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