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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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Cytotoxicity of ZA on breast cancer cells(A+B) High concentrations of ZA affect viability of MCF-7 but not of MDA-MB231. MCF-7 (A) and MDA-MB231 (B) were treated with either 0 μM (circle), 1 μM (square), 3 μM (triangle) or 5 μM (inverse triangle) ZA. Cell proliferation was measured over 72 h using the xCELLigence system and is indicated as cell index. (C+D) Migration capacity of MCF-7 and MDA-MB231 is not affected by ZA. ECM-based migration assays for MCF-7 and MDA-MB231 over 48 h in the absence (gray bars, top pictures) and presence of 2 μM ZA (black bars, bottom pictures). Scale bars indicate 200 μm.
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Figure 1: Cytotoxicity of ZA on breast cancer cells(A+B) High concentrations of ZA affect viability of MCF-7 but not of MDA-MB231. MCF-7 (A) and MDA-MB231 (B) were treated with either 0 μM (circle), 1 μM (square), 3 μM (triangle) or 5 μM (inverse triangle) ZA. Cell proliferation was measured over 72 h using the xCELLigence system and is indicated as cell index. (C+D) Migration capacity of MCF-7 and MDA-MB231 is not affected by ZA. ECM-based migration assays for MCF-7 and MDA-MB231 over 48 h in the absence (gray bars, top pictures) and presence of 2 μM ZA (black bars, bottom pictures). Scale bars indicate 200 μm.

Mentions: To be able to discriminate direct effects of ZA on breast cancer cells from impacts on different macrophage populations, we first analyzed the toxicity of this drug for two human breast cancer cell lines. MCF-7 (luminal A subtype) and MDA-MB231 (basal-like subtype) cells [23, 24] were treated with increasing concentrations of ZA while recording their cell index (proliferation) using the xCELLigence system. MCF-7 cells showed an only moderately reduced cell index when treated with the highest concentration of ZA (5 μM), while the drug did not affect the proliferation of MDA-MB231 at any concentration tested (Fig. 1 A, B). An important characteristic of metastasizing tumor cells is their migratory activity. To further clarify if this capacity is affected by ZA we performed extra-cellular matrix (ECM)-based migration assays and measured the area which the tumor cells covered within 48 h. The results revealed no change in the migration capacity of neither MCF-7 nor MDA-MB231 by treatment with 2 μM ZA (Fig. 1 C-D).


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 breast cancer cells(A+B) High concentrations of ZA affect viability of MCF-7 but not of MDA-MB231. MCF-7 (A) and MDA-MB231 (B) were treated with either 0 μM (circle), 1 μM (square), 3 μM (triangle) or 5 μM (inverse triangle) ZA. Cell proliferation was measured over 72 h using the xCELLigence system and is indicated as cell index. (C+D) Migration capacity of MCF-7 and MDA-MB231 is not affected by ZA. ECM-based migration assays for MCF-7 and MDA-MB231 over 48 h in the absence (gray bars, top pictures) and presence of 2 μM ZA (black bars, bottom pictures). Scale bars indicate 200 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Cytotoxicity of ZA on breast cancer cells(A+B) High concentrations of ZA affect viability of MCF-7 but not of MDA-MB231. MCF-7 (A) and MDA-MB231 (B) were treated with either 0 μM (circle), 1 μM (square), 3 μM (triangle) or 5 μM (inverse triangle) ZA. Cell proliferation was measured over 72 h using the xCELLigence system and is indicated as cell index. (C+D) Migration capacity of MCF-7 and MDA-MB231 is not affected by ZA. ECM-based migration assays for MCF-7 and MDA-MB231 over 48 h in the absence (gray bars, top pictures) and presence of 2 μM ZA (black bars, bottom pictures). Scale bars indicate 200 μm.
Mentions: To be able to discriminate direct effects of ZA on breast cancer cells from impacts on different macrophage populations, we first analyzed the toxicity of this drug for two human breast cancer cell lines. MCF-7 (luminal A subtype) and MDA-MB231 (basal-like subtype) cells [23, 24] were treated with increasing concentrations of ZA while recording their cell index (proliferation) using the xCELLigence system. MCF-7 cells showed an only moderately reduced cell index when treated with the highest concentration of ZA (5 μM), while the drug did not affect the proliferation of MDA-MB231 at any concentration tested (Fig. 1 A, B). An important characteristic of metastasizing tumor cells is their migratory activity. To further clarify if this capacity is affected by ZA we performed extra-cellular matrix (ECM)-based migration assays and measured the area which the tumor cells covered within 48 h. The results revealed no change in the migration capacity of neither MCF-7 nor MDA-MB231 by treatment with 2 μM ZA (Fig. 1 C-D).

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