摘要
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.
原文 | 英語 |
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文章編號 | 10 |
期刊 | Journal of Hematology and Oncology |
卷 | 12 |
發行號 | 1 |
DOIs | |
出版狀態 | 已發佈 - 1月 25 2019 |
ASJC Scopus subject areas
- 分子生物學
- 血液學
- 腫瘤科
- 癌症研究
指紋
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Additional file 4: of Tumor stem-like cell-derived exosomal RNAs prime neutrophils for facilitating tumorigenesis of colon cancer
Lan, H.-Y. (Contributor), Cheng, W.-C. (Contributor), Yang, M.-H. (Contributor), Hwang, W.-L. (Creator) & Huang, S.-C. (Contributor), Figshare, 2019
DOI: 10.6084/m9.figshare.7634912.v1, https://doi.org/10.6084%2Fm9.figshare.7634912.v1
資料集: Dataset
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Additional file 9: of Tumor stem-like cell-derived exosomal RNAs prime neutrophils for facilitating tumorigenesis of colon cancer
Yang, M.-H. (Contributor), Huang, S.-C. (Contributor), Cheng, W.-C. (Contributor), Lan, H.-Y. (Contributor) & Hwang, W.-L. (Creator), Figshare, 2019
DOI: 10.6084/m9.figshare.7634954.v1, https://doi.org/10.6084%2Fm9.figshare.7634954.v1
資料集: Dataset
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Additional file 5: of Tumor stem-like cell-derived exosomal RNAs prime neutrophils for facilitating tumorigenesis of colon cancer
Hwang, W.-L. (Creator), Yang, M.-H. (Contributor), Huang, S.-C. (Contributor), Cheng, W.-C. (Contributor) & Lan, H.-Y. (Contributor), Figshare, 2019
DOI: 10.6084/m9.figshare.7634921.v1, https://doi.org/10.6084%2Fm9.figshare.7634921.v1
資料集: Dataset