Abstract
BackgroundExpression 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.MethodsMonocytes 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).ResultsOct4-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.ConclusionsOur 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.
Highlights
Expression of Oct4 maintains cancer stem cell (CSC)-like properties in lung cancer cells and is correlated with poor prognosis of lung adenocarcinoma
Expression of Oct4 in lung cancer cells induces monocyte differentiation into M2-like macrophages through macrophage colonystimulating factor (M-CSF) secretion As human cancer cell lines are more closely resemble clinical human tumors than murine cancer cell lines, we employed human A549 lung cancer cells to study whether Oct4 expression in cancer cells contributed to macrophage polarization in vitro
The percentages of M2 macrophages were reduced in THP-1 cells cocultured with the conditioned medium obtained from Oct4knockdown A549 cells, as compared with those from the control cells (Fig. 1c)
Summary
Expression of Oct 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. We explored the role of Oct in cytokine secretion in lung cancer and its impact on M2 TAM polarization. It was shown that the numbers of tumor-associated immune cells were significantly greater in stage III than in stage I lung cancer specimens [2]. The roles of tumor-associated macrophages (TAMs) in tumor progression and metastasis have gained much attention [3]. Several studies have shown that monocytes can be recruited to tumor sites through the secretion of various mediators, such as macrophage colonystimulating factor (M-CSF), monocyte chemoattractant protein (MCP)-1, MCP-2, macrophage inflammatory protein (MIP)-1α, and MIP-1β [5]. The Th2 cytokines produced by M2 macrophages act in favor of tumor progression in lung adenocarcinoma [6] and epithelial-mesenchymal transition (EMT) in pancreatic cancer cells [7]. Identification and quantification of these immune cell populations and their roles in lung cancer are currently being investigated
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