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Int J Cancer. 2019 Oct 15;145(8):2209-2224. doi: 10.1002/ijc.32338. Epub 2019 Apr 30.

RAB27B-activated secretion of stem-like tumor exosomes delivers the biomarker microRNA-146a-5p, which promotes tumorigenesis and associates with an immunosuppressive tumor microenvironment in colorectal cancer.

Author information

1
Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
2
Research Center for Tumor Medical Science, China Medical University, Taichung, Taiwan.
3
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
4
Cancer Progression Research Center, National Yang-Ming University, Taipei, Taiwan.
5
Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
6
Department of Medicine, National Yang-Ming University, Taipei, Taiwan.
7
Yuan's General Hospital, Kaohsiung, Taiwan.
8
Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
9
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
10
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
11
Department of Education and Research, Taipei City Hospital, Taipei, Taiwan.
12
Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
13
The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.

Abstract

The dynamic cell-cell communication is essential for tissue homeostasis in normal physiological circumstances and contributes to a diversified tumor microenvironment. Although exosomes are extracellular vesicles that actively participate in cell-cell interaction by shutting cellular components, impacts of tumor exosomes in the context of cancer stemness remain elusive. Here, we expand colorectal cancer stem cells (CRCSCs) as cancer spheroids and demonstrate that the β-catenin/Tcf-4-activated RAB27B expression is required for the secretion of CRCSC exosomes. In an exosomal RNA sequencing analysis, a switch of exosomal RNA species from retrotransposons to microRNAs (miRNAs) is identified upon expanding CRCSCs. miRNA-146a-5p (miR-146a) is the major miRNA in CRCSC exosomes and exosomal miR-146a promotes stem-like properties and tumorigenicity by targeting Numb in recipient CRC cells. Among 53 CRC patients, those with abundant exosomal miR-146a expression in serum exhibits higher miR-146aHigh /NumbLow CRCSC traits, an increased number of tumor-filtrating CD66(+) neutrophils and a decreased number of tumor-infiltrating CD8(+) T cells. Our study elucidates a unique mechanism of tumor exosome-mediated stemness expansion.

KEYWORDS:

cancer stem cells; exosome heterogeneity; microRNA biomarker

PMID:
30980673
DOI:
10.1002/ijc.32338

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