Oncotarget

Research Papers: Immunology:

Modulation of macrophage polarization and lung cancer cell stemness by MUC1 and development of a related small-molecule inhibitor pterostilbene

Wen-Chien Huang, Mei-Lin Chan, Ming-Jen Chen, Tung-Hu Tsai, Yu-Jen Chen _

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Oncotarget. 2016; 7:39363-39375. https://doi.org/10.18632/oncotarget.8101

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Abstract

Wen-Chien Huang1,2,4, Mei-Lin Chan1,2,4, Ming-Jen Chen4,5, Tung-Hu Tsai1,6 and Yu-Jen Chen1,3,4,7

1 MacKay Medical College, Taipei, Taiwan

2 Department of Surgery, Division of Thoracic Surgery, MacKay Memorial Hospital, Taipei, Taiwan

3 Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan

4 Institute of Traditional Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan

5 Department of Surgery, Division of Colorectal Surgery, MacKay Memorial Hospital, Taipei, Taiwan

6 Department of Education and Research, Taipei City Hospital, Taipei, Taiwan

7 College of Chinese Medicine, China Medical University, Taichung, Taiwan

Correspondence to:

Yu-Jen Chen, email:

Tung-Hu Tsai, email:

Keywords: tumor-associated macrophages (TAMs), lung cancer stem cells (CSCs), MUC1, pterostilbene, M2 polarization, Immunology and Microbiology Section, Immune response, Immunity

Received: July 31, 2015 Accepted: May 17, 2016 Published: June 04, 2016

Abstract

Tumor-associated macrophages (TAMs) polarized to the M2 phenotype play key roles in tumor progression in different cancer types, including lung cancer. MUC1 expression in various types of cancer is an indicator of poorer prognosis. Elevated MUC1 expression has been reported in inflammatory lung macrophages and is associated with lung cancer development. Here, we investigated the role of M2-polarized TAMs (M2-TAMs) in the generation of lung cancer stem cells (LCSCs) and tested pterostilbene, a small-molecule agent that modulates MUC1 expression in lung cancer cells, with the goal of subverting the microenvironment toward a favorable anti-tumor impact. We found that MUC1 was overexpressed in lung cancer patients, which was associated with poor survival rates. M2-TAMs and cancer cell lines were co-cultured in an experimental tumor microenvironment model. The expression levels of MUC1 and cancer stemness genes significantly increased in lung cancer cells in the presence of the M2-TAM cells. Intriguingly, pterostilbene dose-dependently suppressed self-renewal ability in M2-TAMs-co-cultured lung cancer cells, and this suppression was accompanied by downregulation of MUC1, NF-κB, CD133, β-catenin, and Sox2 expression. Moreover, MUC1-silenced M2-TAMs exhibited a significantly lower ability to promote LCSC generation and decreased levels of NF-κB, CD133, and Sox2. The results suggest that MUC1 plays an important role in TAM-induced LCSC progression. Pterostilbene may have therapeutic potential for modulating the unfavorable effects of TAMs in lung cancer progression.


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