Enhanced invasion of lung adenocarcinoma cells after co-culture with THP-1-derived macrophages via the induction of EMT by IL-6.
Lung cancer is the leading cause of cancer mortality worldwide, and the cause of death is metastasis. The epithelial-to-mesenchymal transition (EMT) plays a key role in the process of metastasis. Macrophages within the lung cancer microenvironment release cytokines, such as interleukin-6 (IL-6), and promote lung cancer cell invasion and metastasis. However, the interaction between macrophages and lung cancer cells and the effect of this interaction on the expression of IL-6, EMT, and the invasiveness of lung cancer cells remain unclear. Therefore, we established an in vitro co-culture model of human lung adenocarcinoma A549 or H1299 cells with THP-1-derived macrophages to illuminate the important role of macrophages in the invasion of lung cancer. In this study, we demonstrated that the concentrations of IL-6 in the co-culture supernatants were significantly increased compared with controls. Thus, a complex chemical cross-talk is induced by the indirect cell-to-cell contact between lung cancer cells and THP-1-derived macrophages. THP-1-derived macrophages appeared to play an important initiator role in the process. The analysis of the mRNA expression profiles of the sorted cells from the co-culture system revealed that the co-cultured lung cancer cells are the main source of the observed increase in IL-6 secretion. In addition, the interactions between lung cancer cells and THP-1-derived macrophages are bidirectional. The THP-1-derived macrophages underwent differentiation towards the M2-macrophage phenotype during the co-culture process. The expression of IL-6 was correlated with the induction of EMT, which contributed to a significant increase in the invasiveness of the A549 and H1299 cells in vitro. In addition, the addition of an anti-IL-6 antibody reversed these changes. In summary, we demonstrated that the in vitro co-culture of A549 or H1299 cells with THP-1-derived macrophages upregulates IL-6 expression, which increases the invasion ability of the A549 and H1299 cells through the EMT pathway. The THP-1-derived macrophages that interacted with the lung cancer cells differentiated towards the M2-macrophage phenotype. Thus, the inhibition of IL-6 or of the interactions between lung cancer cells and macrophages may be an effective target for anti-cancer therapy in patients with non-small cell lung cancer.
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, PR China.
Che
C
Dehai
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, PR China.
Pan
P
Bo
Department of Respiratory Medicine, The Fifth Affiliated Hospital of Harbin Medical University, Daqing 163000, PR China.
Tian
T
Qiang
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, PR China.
Shang
S
Lihua
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, PR China.
Liu
L
Fang
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, PR China.
Jin
J
Shi
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, PR China.
Cao
C
Jingyan
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, PR China. Electronic address: yy_yuyan@126.com.
Yu
Y
Yan
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, PR China.
Wang
W
Guangbin
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, PR China.
Yuan
Y
Zhenjun
D000230:Adenocarcinoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D010641:Phenotype
D015415:Biomarkers; D015850:Interleukin-6
A549 and H1299 cells; Co-culture; EMT; IL-6; Invasion; THP-1-derived macrophages