期刊
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
卷 42, 期 6, 页码 3395-3403出版社
SPANDIDOS PUBL LTD
DOI: 10.3892/ijmm.2018.3923
关键词
M2 phenotype tumour-associated macrophages; U251 glioma cell; transforming growth factor-beta 1; small mothers against decapentaplegic 2/3; sex determining region Y-box 2; stemness and migration
资金
- Beijing Medical Health Public Welfare Foundation [YWJKJJHKYJJ-B17468]
The positive correlation between the number of M2 phenotype TAMs (M2-TAMs) and tumour development suggests a supportive role of M2-TAMs in glioma progression. In the present study, the molecular link between glioma cells and M2-TAMs was investigated and it was demonstrated that transforming growth factor-beta 1 (TGF-beta 1) secreted by M2-TAMs is key in facilitating the stemness and migration of glioma cells. Cluster of differentiation (CD)133 and CD44, markers for the M2 phenotype, were assessed by western blotting. A sphere formation assay and trans-well assay were applied to test the stemness and migration abilities of glioma cells following co-cultured with M2-TAMs. Stemness markers CD133 and CD44, epithelial-mesenchymal transition-associated markers and mothers against decapentaplegic homolog (SMAD)2/3 and sex determining region Y-box 4/2 (SOX4/2) levels were also evaluated by western blotting. A xenograft tumor mouse model was used to demonstrate the tumor forming ability of glioma cells. The results showed that the U251 glioma cells co-cultured with M2-TAMs exhibited high level of sphere formation, stemness and migration ability. Recombinant TGF-beta 1 protein treatment was able to achieve the same effects on U251 cells, whereas a TGF-beta pathway inhibitor reversed the stemness and migration abilities of the glioma cells induced by M2-TAMs. It was also demonstrated that TGF-beta 1 secreted by M2-TAMs upregulated the phosphorylation of SMAD2/3 and the expression of SOX4/2 in glioma cells. In a mouse xenograft model, solid tumours formed by U251 cells co-cultured with M2-TAMs or pre-treated with TGF-beta 1 were larger in size and had a higher growth rate. Taken together, results of the present study demonstrated that M2-TAMs promoted the stemness and migration abilities of glioma cells by secreting TGF-beta 1, which activated the SMAD2/3 pathway and induced the expression of SOX4 and SOX2. These results highlight the mechanism by which M2-TAMs and glioma interact and demonstrate potential therapeutic strategies for glioma treatment.
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