Tumor stem-like cell-derived exosomal RNAs prime neutrophils for facilitating tumorigenesis of colon cancer

Autor: Wei-Chung Cheng, Shih Ching Huang, Wei Lun Hwang, Hsin Yi Lan, Muh Hwa Yang
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Carcinogenesis
Neutrophils
Colorectal cancer
Interleukin-1beta
Cell Communication
Exosomes
medicine.disease_cause
Mice
0302 clinical medicine
Tumor Microenvironment
Tumor-host interaction
Tissue homeostasis
Mice
Inbred BALB C
Isografts
Cancer stem cells
lcsh:Diseases of the blood and blood-forming organs
Hematology
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Interleukin-1β
Oncology
030220 oncology & carcinogenesis
Colonic Neoplasms
Neoplastic Stem Cells
Stem cell
Cell Survival
Biology
lcsh:RC254-282
03 medical and health sciences
Cancer stem cell
Cell Line
Tumor
Spheroids
Cellular
medicine
Animals
Humans
Molecular Biology
Peroxidase
Tumor microenvironment
Base Sequence
lcsh:RC633-647.5
Research
NF-kappa B p50 Subunit
Cancer
medicine.disease
Microvesicles
HEK293 Cells
030104 developmental biology
Cancer research
RNA
Zdroj: Journal of Hematology & Oncology
Journal of Hematology & Oncology, Vol 12, Iss 1, Pp 1-17 (2019)
ISSN: 1756-8722
Popis: 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+/Ly6GHigh/Ly6CLow 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. Electronic supplementary material The online version of this article (10.1186/s13045-019-0699-4) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
Externí odkaz: