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Published on: October 9, 2013
Microglia promote colonization of brain tissue by breast cancer cells in a Wnt-dependent way
Tobias Pukrop1, Faramarz Dehghani, Han-Ning Chuang
1Department of Hematology/Oncology, University of Göttingen, Göttingen, Germany. tobias.pukrop@med.uni-goettingen.de
Abstract:
Although there is increasing evidence that blood-derived macrophages support tumor progression, it is still unclear whether specialized resident macrophages, such as brain microglia, also play a prominent role in metastasis formation. Here, we show that microglia enhance invasion and colonization of brain tissue by breast cancer cells, serving both as active transporters and guiding rails. This is antagonized by inactivation of microglia as well as by the Wnt inhibitor Dickkopf-2. Proinvasive microglia demonstrate altered morphology, but neither upregulation of M2-like cytokines nor differential gene expression. Bacterial lipopolysacharide shifts tumor-educated microglia into a classical M1 phenotype, reduces their proinvasive function, and unmasks inflammatory and Wnt signaling as the most strongly regulated pathways. Histological findings in human brain metastases underline the significance of these results. In conclusion, microglia are critical for the successful colonization of the brain by epithelial cancer cells, suggesting inhibition of proinvasive microglia as a promising antimetastatic strategy.
Insights
Microglia, specialized brain immune cells, actively assist breast cancer cells in invading and colonizing the brain. Inhibiting these proinvasive microglia may offer a novel anti-metastasis strategy.
Area of Science:
- Neuroscience
- Immunology
- Oncology
Background:
- Blood-derived macrophages are known to promote tumor growth.
- The role of resident brain macrophages (microglia) in brain metastasis is not well understood.
Purpose of the Study:
- To investigate the role of microglia in breast cancer brain metastasis.
- To identify mechanisms by which microglia influence cancer cell invasion and colonization.
Main Methods:
- Utilized in vitro and in vivo models of breast cancer brain metastasis.
- Analyzed microglia morphology and phenotype.
- Investigated the effect of microglia inactivation and Wnt signaling inhibition.
Main Results:
- Microglia actively facilitate breast cancer cell invasion and colonization of brain tissue.
- Microglia inactivation and Wnt pathway inhibition counteract this proinvasive effect.
- Proinvasive microglia exhibit altered morphology but not M2-like cytokine upregulation.
- Bacterial lipopolysaccharide induces an M1 phenotype in microglia, reducing proinvasive function and highlighting inflammatory and Wnt signaling.
Conclusions:
- Microglia are critical for successful brain colonization by epithelial cancer cells.
- Targeting proinvasive microglia represents a potential antimetastatic therapeutic strategy.
