Zoledronic acid inhibits macrophage/microglia-assisted breast cancer cell invasion
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Eva Rietkötter1, Kerstin Menck1, Annalen Bleckmann1,2, Katja Farhat3, Meike Schaffrinski1, Matthias Schulz1, Uwe-Karsten Hanisch4, Claudia Binder1, Tobias Pukrop1
1 Department of Hematology/Oncology, University Medical Center, 37099 Göttingen, Germany
2 Department of Medical Statistics, University Medical Center, 37099 Göttingen, Germany
3 Department of Cardiovascular Physiology, University Medical Center, 37099 Göttingen, Germany
4 Institute of Neuropathology, University Medical Center, 37099 Göttingen, Germany
Tobias Pukrop, email:
Keywords: Zoledronic acid, macrophages, microglia, metastasis, tumor microenvironment
Received: July 23, 2013 Accepted: August 17, 2013 Published: August 19, 2013
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.
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