Journal
NEOPLASIA
Volume 20, Issue 8, Pages 775-788Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neo.2018.06.004
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Funding
- National Health Research Institutes [NHRI-EX107-10622BI]
- Taipei Veterans General Hospital [V107C-071]
- Ministry of Education, High Education Sprout Project
- Ministry of Health and Welfare, Center of Excellence for Cancer Research [MOHW106-TDU-B-211-144-003]
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Epithelial-mesenchymal transition (EMT) is a major event during cancer progression and metastasis; however, the definitive role of EMT in remodeling tumor microenvironments (TMEs) is unclear. Tumor-associated macrophages (TAMs) are a major type of host immune cells in TMEs, and they perform a wide range of functions to regulate tumor colonization and progression by regulating tumor invasiveness, local tumor immunity, and angiogenesis. TAMs are considered to have an M2-like, i.e., alternatively activated, phenotype; however, how these EMT-undergoing cancer cells promote M2 polarization of TAMs as a crucial tumor-host interplay during cancer progression is unclear. In this study, we investigated the mechanism of EMT-mediated TAM activation. Here, we demonstrate that the EMT transcriptional factor Snail directly activates the transcription of MIR21 to produce miR21-abundant tumor-derived exosomes (TEXs). The miR-21-containing exosomes were engulfed by CD14(+) human monocytes, suppressing the expression of M1 markers and increasing that of M2 markers. Knockdown of miR-21 in Snail-expressing human head and neck cancer cells attenuated the Snail-induced M2 polarization, angiogenesis, and tumor growth. In head and neck cancer samples, a high expression of miR-21 was correlated with a higher level of SNAI1 and the M2 marker MRC1. This study elucidates the mechanism of EMT-mediated M2 polarization through delivery of the miR-21-abundant exosomes, which may serve as a candidate biomarker of tumor progression and provide a potential target for intercepting EMT-mediated TME remodeling.
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