Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis
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Coculture Assays to Study Macrophage and Microglia Stimulation of Glioblastoma Invasion
Published on: October 20, 2016
Ying Wang1, Tao Liu2, Ning Yang2
1Department of Rehabilitation, Qilu Children's Hospital of Shandong University, Jinan, Shandong, P.R. China.
Abstract:
Glioblastoma (GBM) is a highly malignant brain tumor characterized by invasion tendency. Macrophage infiltration is associated with GBM invasion, but the mechanisms remain unclear. Hypoxia is an outstanding characteristic of GBM tissue. Hypoxia microenvironment modulates the biological behaviors of both tumor cells and infiltrated immune cells, including macrophages. In the present study, we analyzed the effects of hypoxia and macrophages on invasion of GBM cells and its potential mechanisms. We found that both hypoxia and macrophage supernatant promoted GBM cells invasion and matrix metalloproteinase (MMP)-9 expression, and hypoxia modulated the invasive activity of GBM cells by upregulating their CCR5 expression. The supernatant of hypoxic macrophages also showed greater pro-invasion effect than normoxic macrophages through the elevated secretion of CCL4. Moreover, we found that interferon regulatory factor-8 (IRF-8) was possibly involved in hypoxia-modulated CCL4 expression of macrophages. Taken together, the present study found that macrophages promoted GBM invasion by the CCL4-CCR5 axis, and hypoxia enhanced the interaction between these two types of cells by upregulating both CCL4 and CCR5 expression, respectively. The results of the present study suggested that hypoxia would be a potential target for the development of immune therapies of GBM.
Insights
Hypoxia and macrophages promote glioblastoma invasion via the CCL4-CCR5 axis. Hypoxia enhances this interaction by upregulating both CCL4 and CCR5, suggesting hypoxia as a potential target for glioblastoma immune therapies.
Area of Science:
- Neuro-oncology
- Immunology
- Cancer biology
Background:
- Glioblastoma (GBM) is a highly malignant brain tumor known for its invasive nature.
- Macrophage infiltration is linked to GBM invasion, but the underlying mechanisms are not fully understood.
- The tumor microenvironment in GBM is often characterized by hypoxia, influencing both tumor and immune cells.
Purpose of the Study:
- To investigate the effects of hypoxia and macrophages on glioblastoma cell invasion.
- To elucidate the potential mechanisms involved in hypoxia- and macrophage-mediated GBM invasion.
Main Methods:
- Analysis of glioblastoma cell invasion assays.
- Assessment of matrix metalloproteinase (MMP)-9 expression.
- Evaluation of macrophage supernatant effects on glioblastoma cells.
- Measurement of CCR5 expression in glioblastoma cells.
- Analysis of CCL4 secretion by macrophages under varying oxygen conditions.
- Investigation of interferon regulatory factor-8 (IRF-8) involvement.
Main Results:
- Both hypoxia and macrophage supernatant significantly promoted glioblastoma cell invasion and MMP-9 expression.
- Hypoxia upregulated CCR5 expression in glioblastoma cells, enhancing their invasive activity.
- Hypoxic macrophages secreted more CCL4 than normoxic macrophages, increasing the pro-invasion effect.
- Interferon regulatory factor-8 (IRF-8) may play a role in hypoxia-induced CCL4 expression in macrophages.
Conclusions:
- Macrophages promote glioblastoma invasion through a CCL4-CCR5 signaling axis.
- Hypoxia exacerbates glioblastoma invasion by upregulating both CCL4 and CCR5 expression.
- Targeting hypoxia presents a potential strategy for developing novel immune therapies for glioblastoma.
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