ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1547333
This article is part of the Research TopicNovel Anti-Cancer Agents Targeting Tumour Metastasis and Stemness - Volume IIView all articles
IL6/CCL2 from M2 polarized microglia promotes breast cancer brain metastasis and the reversal effect of β-elemene
Provisionally accepted
- Guangzhou University of Chinese Medicine, Guangzhou, China
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Introduction: Brain 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. Methods: An 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 cells conditioned media and primary microglia co-culture model and 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. Results: BC-BM cells established in our study not only increased BM rates but also exhibit mesenchymal phenotype, and activated JAK-STAT signaling pathway. Microglia, particularly M2-microglia, was enriched in BM lesions and secreted high levels of both of IL6 and CCL2. Hypersecretory IL6 reversed the MET process of BC cells by regulation JAK2/STAT3 singnaling pathway to promote colonization in brain. Increased levels of CCL2 significantly recruited monocytic myeloid-derived suppressor cells (M-MDSC) to induce an immunosuppressive brain microenvironment. β-elemene could significantly inhibit BC-BM in mice by regulating IL6/STAT3 signaling pathway and suppressing M-MDSC recruitment. Conclusion: Our work firstly demonstrated that β-elemene regulated IL6/STAT3 axis and M-MDSC recruitment to reconstruct immunosuppressive brain microenvironment to suppress BC-BM.
Keywords: Breast cancer brain metastasis, M2-microglia, IL6 and CCL2 cytokines, IL6-STAT3 signaling pathway, β-elemene
Received: 18 Dec 2024; Accepted: 15 Apr 2025.
Copyright: © 2025 Zhang, Feng, Li, Zou, Wang, Yang, Zhang and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Rong-Rong Zhang, Guangzhou University of Chinese Medicine, Guangzhou, China
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