Oct4 promotes M2 macrophage polarization through upregulation of macrophage colony-stimulating factor in lung cancer

Abstract

Background 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. Methods 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). Results 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. Conclusions 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.

IL-34 and CSF-1, deciphering similarities and differences at steady state and in diseases

“…Even though the implication of CSF‐1 appears to be minor, a recent paper demonstrated that lung cancer cells expressing Oct4 stimulated the secretion of CSF‐1. As a consequence, CSF‐1 promoted M2 macrophages polarization leading to tumor growth and metastasis 103 .…”

The Pro-Survival Oct4/Stat1/Mcl-1 Axis Is Associated with Poor Prognosis in Lung Adenocarcinoma Patients

“…Moreover, Oct4 is involved in modulating the tumor microenvironment. Oct4 promotes M2 polarization by increasing M-CSF secretion, thus stimulating tumor metastasis [12]. These data imply the critical role of Oct4 in tumor metastasis.…”

“…Given that apoptosis causes the least immune reaction [24], it is critical to better understand the anti-apoptotic mechanism in order to develop effective strategies for cancer treatment. Previous studies have revealed that both Oct4 and Stat1 are overexpressed in lung adenocarcinoma and might play a role in cell survival [7,12,16,17]. Computational analysis shows that Oct4 may bind to the Stat1 promoter to transactivate Stat1 gene expression.…”

Next frontier in tumor immunotherapy: macrophage-mediated immune evasion

“…After M-CSF binds to its receptor, downstream pathways PKC, PI3K and SFK could be activated to promote the migration of macrophages to tumor areas and transform them into M2 phenotype, and as mentioned earlier, they can also regulate the secretion of VEGF by macrophages and promote tumor angiogenesis [ 57 , 58 ]. For example, lung cancer cells express Oct4 to up-regulate the secretion of M-CSF, promoting M2 polarization, leading to cancer growth and metastasis, which has been verified in syngeneic mouse lung tumor model and clinical samples of non-small cell lung cancer [ 59 ]. Analogously, based on athymic BALB/c mouse model and RCC cell line, researchers found that RCC cells co-expressed M-CSF and its receptor.…”