M2-like tumor-associated macrophage-secreted CCL2 facilitates gallbladder cancer stemness and metastasis

作者：Weihong Chen, Ming‐Yuan Chen, Lingju Hong, Abudukeremu Xiahenazi, Maotuan Huang, Nanhong Tang, Xinyue Yang, Feifei She, Yanling Chen · 发表于：Experimental Hematology and Oncology · 年份：2024 · DOI：10.1186/s40164-024-00550-2 · 被引用次数：38 · 研究领域：Immune cells in cancer、Cancer Cells and Metastasis、Cholangiocarcinoma and Gallbladder Cancer Studies

BACKGROUND: The predominant immune cells in solid tumors are M2-like tumor-associated macrophages (M2-like TAMs), which significantly impact the promotion of epithelial-mesenchymal transition (EMT) in tumors, enhancing stemness and facilitating tumor invasion and metastasis. However, the contribution of M2-like TAMs to tumor progression in gallbladder cancer (GBC) is partially known. METHODS: Immunohistochemistry was used to evaluate the expression of M2-like TAMs and cancer stem cell (CSC) markers in 24 pairs of GBC and adjacent noncancerous tissues from patients with GBC. Subsequently, GBC cells and M2-like TAMs were co-cultured to examine the expression of CSC markers, EMT markers, and migratory behavior. Proteomics was performed on the culture supernatant of M2-like TAMs. The mechanisms underlying the induction of EMT, stemness, and metastasis in GBC by M2-like TAMs were elucidated using proteomics and transcriptomics. GBC cells were co-cultured with undifferentiated macrophages (M0) and analyzed. The therapeutic effect of gemcitabine combined with a chemokine (C-C motif) receptor 2 (CCR2) antagonist on GBC was observed in vivo. RESULTS: The expression levels of CD68 and CD163 in M2-like TAMs and CD44 and CD133 in gallbladder cancer stem cells (GBCSCs) were increased and positively correlated in GBC tissues compared with those in neighboring noncancerous tissues. M2-like TAMs secreted a significant amount of chemotactic cytokine ligand 2 (CCL2), which activated the MEK/ex...