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Zoledronic acid inhibits macrophage/microglia-assisted breast cancer cell invasion.

Rietkötter E, Menck K, Bleckmann A, Farhat K, Schaffrinski M, Schulz M, Hanisch UK, Binder C, Pukrop T - Oncotarget (2013)

Bottom Line: In line with this, manipulation of microglia by ZA in organotypic brain slice cocultures reduced the tissue invasion by carcinoma 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology/Oncology, University Medical Center, 37099 Göttingen, Germany.

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.

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Related in: MedlinePlus

Cytotoxicity of ZA on macrophages(A) Human macrophages (MAC), (B) microglia (MG) and (C) BMDM were treated with either 0 μM (circle), 1 μM (square), 3 μM (triangle) or 5 μM (inverse triangle) ZA. Cell proliferation/morphology was measured over 72 h using the xCELLigence system and is indicated as cell index. While viability of MAC is affected dose-dependently by ZA, viability of MG and BMDM is affected at the lowest concentration tested after 36 h and 48 h treatment, respectively.
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Figure 2: Cytotoxicity of ZA on macrophages(A) Human macrophages (MAC), (B) microglia (MG) and (C) BMDM were treated with either 0 μM (circle), 1 μM (square), 3 μM (triangle) or 5 μM (inverse triangle) ZA. Cell proliferation/morphology was measured over 72 h using the xCELLigence system and is indicated as cell index. While viability of MAC is affected dose-dependently by ZA, viability of MG and BMDM is affected at the lowest concentration tested after 36 h and 48 h treatment, respectively.

Mentions: Since ZA cannot pass the plasma membrane passively but is internalized by endocytosis we hypothesized that macrophages are more sensitive to ZA. To prove this we treated three different macrophage populations with increasing concentration of ZA. The xCELLigence measurements revealed that all three populations were sensitive to ZA already at the lowest concentration tested. ZA decreased the cell index for human macrophages in a dose dependent manner (Fig. 2 A). Notably, murine microglia and BMDM were already completely inhibited by ZA at the lowest concentration. (1 μM) after 36 h and 48 h of treatment, respectively (Fig 2 B, C). This is in great contrast to the results obtained with the cancer cells supporting our hypothesis that the anti-tumor effects of ZA could be mediated by an inhibition of different macrophage-like populations.


Zoledronic acid inhibits macrophage/microglia-assisted breast cancer cell invasion.

Rietkötter E, Menck K, Bleckmann A, Farhat K, Schaffrinski M, Schulz M, Hanisch UK, Binder C, Pukrop T - Oncotarget (2013)

Cytotoxicity of ZA on macrophages(A) Human macrophages (MAC), (B) microglia (MG) and (C) BMDM were treated with either 0 μM (circle), 1 μM (square), 3 μM (triangle) or 5 μM (inverse triangle) ZA. Cell proliferation/morphology was measured over 72 h using the xCELLigence system and is indicated as cell index. While viability of MAC is affected dose-dependently by ZA, viability of MG and BMDM is affected at the lowest concentration tested after 36 h and 48 h treatment, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824537&req=5

Figure 2: Cytotoxicity of ZA on macrophages(A) Human macrophages (MAC), (B) microglia (MG) and (C) BMDM were treated with either 0 μM (circle), 1 μM (square), 3 μM (triangle) or 5 μM (inverse triangle) ZA. Cell proliferation/morphology was measured over 72 h using the xCELLigence system and is indicated as cell index. While viability of MAC is affected dose-dependently by ZA, viability of MG and BMDM is affected at the lowest concentration tested after 36 h and 48 h treatment, respectively.
Mentions: Since ZA cannot pass the plasma membrane passively but is internalized by endocytosis we hypothesized that macrophages are more sensitive to ZA. To prove this we treated three different macrophage populations with increasing concentration of ZA. The xCELLigence measurements revealed that all three populations were sensitive to ZA already at the lowest concentration tested. ZA decreased the cell index for human macrophages in a dose dependent manner (Fig. 2 A). Notably, murine microglia and BMDM were already completely inhibited by ZA at the lowest concentration. (1 μM) after 36 h and 48 h of treatment, respectively (Fig 2 B, C). This is in great contrast to the results obtained with the cancer cells supporting our hypothesis that the anti-tumor effects of ZA could be mediated by an inhibition of different macrophage-like populations.

Bottom Line: In line with this, manipulation of microglia by ZA in organotypic brain slice cocultures reduced the tissue invasion by carcinoma 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology/Oncology, University Medical Center, 37099 Göttingen, Germany.

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.

Show MeSH
Related in: MedlinePlus