IL6/CCL2 from M2-polarized microglia promotes breast cancer brain metastasis and the reversal effect of β-elemene
IntroductionBrain metastasis (BM) is the most common and serious complication of breast cancer (BC). There is significant interest in investigating the crosstalk between BC cells and immune cells. β-elemene is the main pharmacodynamic component of Curcumae Rhizoma, a traditional Chinese medicine tha...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1547333/full |
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| author | Qian Feng Cai-Zhi Li Yi-Hua Zou Xue-Yu Wang Xia Yang Rong Zhang Zhong-Qiu Liu Rong-Rong Zhang |
| author_facet | Qian Feng Cai-Zhi Li Yi-Hua Zou Xue-Yu Wang Xia Yang Rong Zhang Zhong-Qiu Liu Rong-Rong Zhang |
| author_sort | Qian Feng |
| collection | DOAJ |
| description | IntroductionBrain metastasis (BM) is the most common and serious complication of breast cancer (BC). There is significant interest in investigating the crosstalk between BC cells and immune cells. β-elemene is the main pharmacodynamic component of Curcumae Rhizoma, a traditional Chinese medicine that is commonly used for the clinical treatment and prevention of various tumors. However, the specific underlying mechanism of β-elemene in BC-BM is still unclear.MethodsAn intracardiac (ICT) injection model was used to establish specific BC-BM cells, then an intracarotid (ICD) injection model was used to verify the inhibitory effect of β-elemene in BC-BM. Tumor-cell-conditioned media, a primary microglia co-culture model, and an in vitro recruitment experiment were used to explore crosstalk between BC cells and immune cells. TMT-based quantitative proteomic, ELISA, IF, and other molecular biotechnologies were used to investigate the mechanisms.ResultsThe BC-BM cells established in our study not only increased BM rates but also exhibit mesenchymal phenotype and activated the JAK–STAT signaling pathway. Microglia, particularly M2 microglia, were enriched in BM lesions and secreted high levels of both IL6 and CCL2. Hypersecretory IL6 reversed the MET process of BC cells by regulating the JAK2/STAT3 signaling pathway to promote colonization in the brain. Increased levels of CCL2 significantly recruited monocytic myeloid-derived suppressor cells (M-MDSCs) to induce an immunosuppressive brain microenvironment. β-elemene could significantly inhibit BC-BM in mice by regulating the IL6/STAT3 signaling pathway and suppressing the M-MDSC recruitment.ConclusionOur work first demonstrated that β-elemene regulated the IL6/STAT3 axis and M-MDSC recruitment to reconstruct immunosuppressive brain microenvironment to suppress BC-BM. |
| format | Article |
| id | doaj-art-6ac2e5e68a77417fbea62d1ea7c65976 |
| institution | DOAJ |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-6ac2e5e68a77417fbea62d1ea7c659762025-08-20T03:10:06ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-05-011610.3389/fphar.2025.15473331547333IL6/CCL2 from M2-polarized microglia promotes breast cancer brain metastasis and the reversal effect of β-elemeneQian FengCai-Zhi LiYi-Hua ZouXue-Yu WangXia YangRong ZhangZhong-Qiu LiuRong-Rong ZhangIntroductionBrain metastasis (BM) is the most common and serious complication of breast cancer (BC). There is significant interest in investigating the crosstalk between BC cells and immune cells. β-elemene is the main pharmacodynamic component of Curcumae Rhizoma, a traditional Chinese medicine that is commonly used for the clinical treatment and prevention of various tumors. However, the specific underlying mechanism of β-elemene in BC-BM is still unclear.MethodsAn intracardiac (ICT) injection model was used to establish specific BC-BM cells, then an intracarotid (ICD) injection model was used to verify the inhibitory effect of β-elemene in BC-BM. Tumor-cell-conditioned media, a primary microglia co-culture model, and an in vitro recruitment experiment were used to explore crosstalk between BC cells and immune cells. TMT-based quantitative proteomic, ELISA, IF, and other molecular biotechnologies were used to investigate the mechanisms.ResultsThe BC-BM cells established in our study not only increased BM rates but also exhibit mesenchymal phenotype and activated the JAK–STAT signaling pathway. Microglia, particularly M2 microglia, were enriched in BM lesions and secreted high levels of both IL6 and CCL2. Hypersecretory IL6 reversed the MET process of BC cells by regulating the JAK2/STAT3 signaling pathway to promote colonization in the brain. Increased levels of CCL2 significantly recruited monocytic myeloid-derived suppressor cells (M-MDSCs) to induce an immunosuppressive brain microenvironment. β-elemene could significantly inhibit BC-BM in mice by regulating the IL6/STAT3 signaling pathway and suppressing the M-MDSC recruitment.ConclusionOur work first demonstrated that β-elemene regulated the IL6/STAT3 axis and M-MDSC recruitment to reconstruct immunosuppressive brain microenvironment to suppress BC-BM.https://www.frontiersin.org/articles/10.3389/fphar.2025.1547333/fullbreast cancer brain metastasisM2 microgliaIL6 and CCL2 cytokinesIL6-STAT3 signaling pathwayβ-elemene |
| spellingShingle | Qian Feng Cai-Zhi Li Yi-Hua Zou Xue-Yu Wang Xia Yang Rong Zhang Zhong-Qiu Liu Rong-Rong Zhang IL6/CCL2 from M2-polarized microglia promotes breast cancer brain metastasis and the reversal effect of β-elemene Frontiers in Pharmacology breast cancer brain metastasis M2 microglia IL6 and CCL2 cytokines IL6-STAT3 signaling pathway β-elemene |
| title | IL6/CCL2 from M2-polarized microglia promotes breast cancer brain metastasis and the reversal effect of β-elemene |
| title_full | IL6/CCL2 from M2-polarized microglia promotes breast cancer brain metastasis and the reversal effect of β-elemene |
| title_fullStr | IL6/CCL2 from M2-polarized microglia promotes breast cancer brain metastasis and the reversal effect of β-elemene |
| title_full_unstemmed | IL6/CCL2 from M2-polarized microglia promotes breast cancer brain metastasis and the reversal effect of β-elemene |
| title_short | IL6/CCL2 from M2-polarized microglia promotes breast cancer brain metastasis and the reversal effect of β-elemene |
| title_sort | il6 ccl2 from m2 polarized microglia promotes breast cancer brain metastasis and the reversal effect of β elemene |
| topic | breast cancer brain metastasis M2 microglia IL6 and CCL2 cytokines IL6-STAT3 signaling pathway β-elemene |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1547333/full |
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