TY - JOUR
T1 - Tumor stem-like cell-derived exosomal RNAs prime neutrophils for facilitating tumorigenesis of colon cancer
AU - Hwang, Wei Lun
AU - Lan, Hsin Yi
AU - Cheng, Wei Chung
AU - Huang, Shih Ching
AU - Yang, Muh Hwa
N1 - Funding Information:
The authors would like to dedicate this paper to the memory of Prof. Hsei-Wei Wang (National Yang-Ming University), who passed away during the period of this research. This paper could not have been completed without his long-lasting devotion to cancer genomics research. We would like to express our appreciation for the assistance of the Biobank at Taipei Veterans General Hospital for human specimens. This work was supported by the Cancer Progression Research Center, National Yang-Ming University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. We thank Dr. Chi-Hung Lin (Institute of Microbiology and Immunology, National Yang-Ming University) for providing a CT26 cell line and Nature Editing Services for writing assistance.
Funding Information:
This work is supported by Taipei Medical University (TMU104-AE1-B11 to W-L.H), Yuan’s General Hospital (106YGH-TMU-02 to W-L.H), Ministry of Science and Technology (104-2321-B-010-005 and 104-0210-01-09-02 to M-H.Y.; 105-2320-B-038-009-MY2 and MOST106-2628-B-010-005-MY3 to W-L.H.), and a grant from Ministry of Health and Welfare, Center of Excellence for Cancer Research (MOHW107-TDU-B-211-114019 to M-H.Y.).
Publisher Copyright:
© 2019 The Author(s).
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/1/25
Y1 - 2019/1/25
N2 - Background: Cell-cell interactions maintain tissue homeostasis and contribute to dynamic alteration of the tumor microenvironment (TME). Communication between cancer and host cells not only promotes advanced disease aggression but also determines therapeutic response in cancer patients. Despite accumulating evidence supporting the role of tumor-infiltrating immunocytes in modulating tumor immunity, the interplay between heterogeneous tumor subpopulations and immunocytes is elusive. Methods: We expanded colorectal cancer stem cells (CRCSCs) as cancer spheroids from the murine colorectal cancer (CRC) cell line CT26 to interrogate tumor-host interactions using a syngeneic tumor model. RNA-sequencing analysis of host cells and tumor exosomes was performed to identify molecular determinants that mediate the crosstalk between CRCSCs and immunocytes. The Cancer Genome Atlas (TCGA) database was used to validate the clinical significance in CRC patients. Results: The expanded CT26 cancer spheroids showed increased stemness gene expression, enhanced spheroid and clonogenicity potential, and an elevated tumor-initiating ability, characteristic of CRCSCs. By examining immune cell composition in syngeneic tumor-bearing mice, a systemic increase in CD11b + /Ly6G High /Ly6C Low neutrophils was observed in mice bearing CRCSC-derived tumors. An increased secretion of CRCSC exosomes was observed in vitro, and through in vivo tracking, CRCSC exosomes were found to be transported to the bone marrow. Moreover, CRCSC exosomes prolonged the survival of bone marrow-derived neutrophils and engendered a protumoral phenotype in neutrophils. Mechanistically, tumor exosomal tri-phosphate RNAs induced the expression of interleukin-1β (IL-1β) through a pattern recognition-NF-κB signaling axis to sustain neutrophil survival. CRCSC-secreted CXCL1 and CXCL2 then attracted CRCSC-primed neutrophils to promote tumorigenesis of CRC cells via IL-1β. Moreover, neutrophil depletion using a Ly6G-specific antibody (clone 1A8) attenuated the tumorigenicity of CRCSCs. In human specimens, CRC patients exhibiting an active CRCSC signal (Snail + IL8 + ) showed elevated tumor infiltration of MPO + neutrophils, and high (in the top 10%) MPO expression predicted poor survival of CRC patients. Conclusions: This study elucidates a multistep CRCSC-neutrophil interaction during advanced cancer progression. Strategies targeting aberrant neutrophil activation may be developed for combating CSC-related malignancy.
AB - Background: Cell-cell interactions maintain tissue homeostasis and contribute to dynamic alteration of the tumor microenvironment (TME). Communication between cancer and host cells not only promotes advanced disease aggression but also determines therapeutic response in cancer patients. Despite accumulating evidence supporting the role of tumor-infiltrating immunocytes in modulating tumor immunity, the interplay between heterogeneous tumor subpopulations and immunocytes is elusive. Methods: We expanded colorectal cancer stem cells (CRCSCs) as cancer spheroids from the murine colorectal cancer (CRC) cell line CT26 to interrogate tumor-host interactions using a syngeneic tumor model. RNA-sequencing analysis of host cells and tumor exosomes was performed to identify molecular determinants that mediate the crosstalk between CRCSCs and immunocytes. The Cancer Genome Atlas (TCGA) database was used to validate the clinical significance in CRC patients. Results: The expanded CT26 cancer spheroids showed increased stemness gene expression, enhanced spheroid and clonogenicity potential, and an elevated tumor-initiating ability, characteristic of CRCSCs. By examining immune cell composition in syngeneic tumor-bearing mice, a systemic increase in CD11b + /Ly6G High /Ly6C Low neutrophils was observed in mice bearing CRCSC-derived tumors. An increased secretion of CRCSC exosomes was observed in vitro, and through in vivo tracking, CRCSC exosomes were found to be transported to the bone marrow. Moreover, CRCSC exosomes prolonged the survival of bone marrow-derived neutrophils and engendered a protumoral phenotype in neutrophils. Mechanistically, tumor exosomal tri-phosphate RNAs induced the expression of interleukin-1β (IL-1β) through a pattern recognition-NF-κB signaling axis to sustain neutrophil survival. CRCSC-secreted CXCL1 and CXCL2 then attracted CRCSC-primed neutrophils to promote tumorigenesis of CRC cells via IL-1β. Moreover, neutrophil depletion using a Ly6G-specific antibody (clone 1A8) attenuated the tumorigenicity of CRCSCs. In human specimens, CRC patients exhibiting an active CRCSC signal (Snail + IL8 + ) showed elevated tumor infiltration of MPO + neutrophils, and high (in the top 10%) MPO expression predicted poor survival of CRC patients. Conclusions: This study elucidates a multistep CRCSC-neutrophil interaction during advanced cancer progression. Strategies targeting aberrant neutrophil activation may be developed for combating CSC-related malignancy.
KW - Cancer stem cells
KW - Exosomes
KW - Interleukin-1β
KW - Neutrophils
KW - Tumor-host interaction
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U2 - 10.1186/s13045-019-0699-4
DO - 10.1186/s13045-019-0699-4
M3 - Article
C2 - 30683126
AN - SCOPUS:85060557717
VL - 12
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
SN - 1756-8722
IS - 1
M1 - 10
ER -