Modulation of macrophage polarization and lung cancer cell stemness by MUC1 and development of a related small-molecule inhibitor pterostilbene.
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.
MacKay Medical College, Taipei, Taiwan.|Department of Surgery, Division of Thoracic Surgery, MacKay Memorial Hospital, Taipei, Taiwan.|Institute of Traditional Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan.
Wen-Chien
WC
Huang
MacKay Medical College, Taipei, Taiwan.|Department of Surgery, Division of Thoracic Surgery, MacKay Memorial Hospital, Taipei, Taiwan.|Institute of Traditional Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan.
Mei-Lin
ML
Chan
Institute of Traditional Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan.|Department of Surgery, Division of Colorectal Surgery, MacKay Memorial Hospital, Taipei, Taiwan.
Ming-Jen
MJ
Chen
MacKay Medical College, Taipei, Taiwan.|Department of Education and Research, Taipei City Hospital, Taipei, Taiwan.
Tung-Hu
TH
Tsai
MacKay Medical College, Taipei, Taiwan.|Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan.|Institute of Traditional Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan.|College of Chinese Medicine, China Medical University, Taichung, Taiwan.
Yu-Jen
YJ
Chen
D000072283:A549 Cells; D000071916:AC133 Antigen / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002469:Cell Separation; D018920:Coculture Techniques; D018450:Disease Progression; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D007107:Immune System; D007249:Inflammation; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D018396:Mucin-1 / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology*; D010641:Phenotype; D011379:Prognosis; D013267:Stilbenes / Q000494:pharmacology*; D016896:Treatment Outcome; D059016:Tumor Microenvironment
D000071916:AC133 Antigen; C060192:MUC1 protein, human; D018396:Mucin-1; C000606023:PROM1 protein, human; D013267:Stilbenes; C107773:pterostilbene
Immune response; Immunity; Immunology and Microbiology Section; M2 polarization; MUC1; lung cancer stem cells (CSCs); pterostilbene; tumor-associated macrophages (TAMs)