Dehai Che, Bo Pan, Qiang Tian, Lihua Shang, Fang Liu, Shi Jin, Jingyan Cao, Yan Yu, Guangbin Wang, Zhenjun Yuan
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, PR China.
Department of Respiratory Medicine, The Fifth Affiliated Hospital of Harbin Medical University, Daqing 163000, PR China.
Immunol Lett. 2014 Jul;160(1):1-10. doi: 10.1016/j.imlet.2014.03.004. Epub 2014 Mar 31.
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.
肺癌是全球癌症死亡的主要原因，其死因是转移。上皮-间质转化（EMT）在转移过程中起关键作用。肺癌微环境中的巨噬细胞释放细胞因子，如白细胞介素-6（IL-6），并促进肺癌细胞的侵袭和转移。然而，巨噬细胞与肺癌细胞之间的相互作用以及这种相互作用对IL-6表达、EMT和肺癌细胞侵袭性的影响仍不清楚。因此，我们建立了人肺腺癌A549或H1299细胞与THP-1衍生巨噬细胞的体外共培养模型，以阐明巨噬细胞在肺癌侵袭中的重要作用。在本研究中，我们证明与对照组相比，共培养上清液中IL-6的浓度显著增加。因此，肺癌细胞与THP-1衍生巨噬细胞之间的间接细胞间接触诱导了复杂的化学信号交流。THP-1衍生巨噬细胞似乎在这一过程中起重要的起始作用。对共培养系统中分选细胞的mRNA表达谱分析表明，共培养的肺癌细胞是观察到的IL-6分泌增加的主要来源。此外，肺癌细胞与THP-1衍生巨噬细胞之间的相互作用是双向的。在共培养过程中，THP-1衍生巨噬细胞向M2巨噬细胞表型分化。IL-6的表达与EMT的诱导相关，这导致A549和H1299细胞在体外的侵袭性显著增加。此外，添加抗IL-6抗体可逆转这些变化。总之，我们证明A549或H1299细胞与THP-1衍生巨噬细胞的体外共培养上调了IL-6的表达，IL-6通过EMT途径增加了A549和H1299细胞的侵袭能力。与肺癌细胞相互作用的THP-1衍生巨噬细胞向M2巨噬细胞表型分化。因此，抑制IL-6或肺癌细胞与巨噬细胞之间的相互作用可能是非小细胞肺癌患者抗癌治疗的有效靶点。
