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

Chia Sing Lu, Ai Li Shiau, Bing Hua Su, Bing Hua Su, Tsui Shan Hsu, Chung Teng Wang, Yu Chu Su, Ming Shian Tsai, Yin Hsun Feng, Yau Lin Tseng, Yi Ting Yen, Chao Liang Wu, Gia Shing Shieh, Gia Shing Shieh

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number62
JournalJournal of Hematology and Oncology
Volume13
Issue number1
DOIs
Publication statusPublished - 2020 Jun 1

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Hematology
  • Oncology
  • Cancer Research

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