Tumor-associated macrophages promote epithelial-mesenchymal transition and the cancer stem cell properties in triple-negative breast cancer through CCL2/AKT/β-catenin signaling.

Abstract

BACKGROUND:

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor prognosis and limited treatment. As a major component of the tumor microenvironment, tumor-associated macrophages (TAMs) play an important role in facilitating the aggressive behavior of TNBC. This study aimed to explore the novel mechanism of TAMs in the regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties in TNBC.

METHODS:

Expression of the M2-like macrophage marker CD163 was evaluated by immunohistochemistry in human breast cancer tissues. The phenotype of M2 macrophages polarized from Tohoku-Hospital-Pediatrics-1 (THP1) cells was verified by flow cytometry. Transwell assays, wound healing assays, western blotting, flow cytometry, ELISA, quantitative polymerase chain reaction (qPCR), luciferase reporter gene assays, and immunofluorescence assays were conducted to investigate the mechanism by which TAMs regulate EMT and CSC properties in BT549 and HCC1937 cells.

RESULTS:

Clinically, we observed a high infiltration of M2-like tumor-associated macrophages in TNBC tissues and confirmed that TAMs were associated with unfavorable prognosis in TNBC patients. Moreover, we found that conditioned medium from M2 macrophages (M2-CM) markedly promoted EMT and CSC properties in BT549 and HCC1937 cells. Mechanistically, we demonstrated that chemokine (C-C motif) ligand 2 (CCL2) secretion by TAMs activated Akt signaling, which in turn increased the expression and nuclear localization of β-catenin. Furthermore, β-catenin knockdown reversed TAM-induced EMT and CSC properties.

CONCLUSIONS:

This study provides a novel mechanism by which TAMs promote EMT and enhance CSC properties in TNBC via activation of CCL2/AKT/β-catenin signaling, which may offer new strategies for the diagnosis and treatment of TNBC. Video Abstract.

• Authors: Xiangzhou Chen, Mingqiang Yang, Jiang Yin, Pan Li, Shanshan Zeng, Guopei Zheng, Zhimin He, Hao Liu, Qian Wang, Fan Zhang, Danyang Chen
• Journal: Cell communication and signaling : CCS (Cell Commun Signal) Vol. 20 Issue 1 Pg. 92 (06 17 2022) ISSN: 1478-811X [Electronic] England
• PMID: 35715860 (Publication Type: Journal Article, Video-Audio Media, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• CCL2 protein, human
• CTNNB1 protein, human
• Chemokine CCL2
• beta Catenin
• Proto-Oncogene Proteins c-akt

Topics

• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Chemokine CCL2 (metabolism)
• Epithelial-Mesenchymal Transition
• Humans
• Neoplastic Stem Cells (metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Triple Negative Breast Neoplasms (metabolism, pathology)
• Tumor Microenvironment
• Tumor-Associated Macrophages (metabolism, pathology)
• beta Catenin (metabolism)