Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, 1, University Road, Tainan, Taiwan.
Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
J Hematol Oncol. 2020 Jun 1;13(1):62. doi: 10.1186/s13045-020-00887-1.
Expression of Oct4 maintains cancer stem cell (CSC)-like properties in lung cancer cells and is correlated with poor prognosis of lung adenocarcinoma. M2-type tumor-associated macrophages (TAMs) promote cancer cell migration and metastasis. Tumor microenvironments promote monocyte differentiation into M2 TAMs via a complex cytokine-based connection. We explored the role of Oct4 in cytokine secretion in lung cancer and its impact on M2 TAM polarization.
Monocytes co-cultured with the conditioned medium from Oct4-overexpressing lung cancer cells were used to investigate M2 TAM differentiation. The inflammatory factors in the conditioned medium of Oct4-overexpressing A549 cells were examined using human inflammation antibody arrays. The correlations of Oct4, macrophage colony-stimulating factor (M-CSF), and M2 TAMs were validated in lung cancer cells, syngeneic mouse lung tumor models, and clinical samples of non-small cell lung cancer (NSCLC).
Oct4-overexpressing A549 cells expressed elevated levels of M-CSF, which contributed to increased M2 macrophages and enhanced tumor migration. Overexpression of Oct4 enhanced tumor growth and reduced the survival of lung tumor-bearing mice, which was correlated with increased number of M2 macrophages in lung cancer. Notably, NSCLC patients with high expression levels of Oct4, M-CSF, and M2 TAMs had the poorest recurrence-free survival. A positive correlation between Oct4, M-CSF, and M2 TAMs was observed in the tumor tissue of NSCLC patient. Treatment with all-trans retinoic acid exerted anti-tumor effects and reduced M2 TAMs in tumor-bearing mice.
Our results indicate that Oct4 expressed by lung cancer cells promotes M2 macrophage polarization through upregulation of M-CSF secretion, leading to cancer growth and metastasis. Our findings also implicate that the Oct4/M-CSF axis in M2 macrophage polarization may be potential therapeutic targets for lung cancer.
Oct4 表达维持肺癌细胞中的癌症干细胞（CSC）样特性，并与肺腺癌的不良预后相关。M2 型肿瘤相关巨噬细胞（TAMs）促进癌细胞迁移和转移。肿瘤微环境通过基于复杂细胞因子的连接促进单核细胞分化为 M2 TAMs。我们探讨了 Oct4 在肺癌中细胞因子分泌中的作用及其对 M2 TAM 极化的影响。
用过表达 Oct4 的肺癌细胞的条件培养基共培养单核细胞，以研究 M2 TAM 分化。用人类炎症抗体阵列检测过表达 Oct4 的 A549 细胞条件培养基中的炎症因子。在肺癌细胞、同基因小鼠肺肿瘤模型和非小细胞肺癌（NSCLC）的临床样本中验证了 Oct4、巨噬细胞集落刺激因子（M-CSF）和 M2 TAMs 的相关性。
过表达 Oct4 的 A549 细胞表达升高的 M-CSF，导致 M2 巨噬细胞增加和肿瘤迁移增强。Oct4 的过表达增强了肿瘤生长并降低了荷瘤小鼠的存活率，这与肺癌中 M2 巨噬细胞数量的增加相关。值得注意的是，NSCLC 患者中 Oct4、M-CSF 和 M2 TAMs 表达水平高的患者无复发生存期最差。在 NSCLC 患者的肿瘤组织中观察到 Oct4、M-CSF 和 M2 TAMs 之间存在正相关。全反式维甲酸治疗在荷瘤小鼠中发挥了抗肿瘤作用并减少了 M2 TAMs。
我们的研究结果表明，肺癌细胞表达的 Oct4 通过上调 M-CSF 分泌促进 M2 巨噬细胞极化，导致癌症生长和转移。我们的研究结果还表明，Oct4/M-CSF 轴在 M2 巨噬细胞极化中可能是肺癌的潜在治疗靶点。
