Granulocytic Myeloid-Derived Suppressor Cells Promote the Stemness of Colorectal Cancer Cells through Exosomal S100A9.

Yungang Wang,Shengjun Wang,Jie Ma,Huaxi Xu,Xueli Xia,Kai Yin,Xinyi Tang,Jie Tian

doi:10.1002/advs.201901278

Abstract

Cancer stem cells play a critical role in colorectal cancer (CRC) progression. Myeloid‐derived suppressor cells (MDSCs) promote tumor progression through multiple mechanisms in CRC. The roles of MDSCs in CRC cell stemness are unclear. MDSC‐derived exosomes are proposed to act as intercellular messengers. Herein, it is reported that granulocytic MDSCs (G‐MDSCs) promote CRC cell stemness and progression in mice through exosomes. It is found that S100A9, is highly expressed in G‐MDSC‐derived exosomes, and its blockade suppresses CRC cell stemness and the susceptibility of mice to AOM/DSS‐induced colitis‐associated colon cancer. Hypoxia induces G‐MDSCs to secrete more exosomes in a hypoxia‐inducible factor 1α (HIF‐1α)‐dependent manner, and respiratory hyperoxia can reduce CRC cells stemness through the inhibition of GM‐Exo production. Study‐based CRC patients also show that human MDSCs enhance CRC cell stemness and growth via exosomal S100A9, and plasma exosomal S100A9 level in CRC patients is markedly higher than that in healthy subjects. Thus, this study suggests that G‐MDSCs promote CRC cell stemness and growth through exosomal S100A9. Moreover, respiratory hyperoxia may be a beneficial strategy to reduce CRC cells stemness through the inhibition of GM‐Exo production. MDSCs exosomal S100A9 may be a marker for predicting the development of CRC.

Highlights

We demonstrate that hypoxia plays a key role in exosomes secretion from G-MDSCs through promoting Rab27a expression and respiratory hyperoxia reduces colon cancer cells stemness through inhibiting G-MDSC exosomes (GM-Exo) production
To determine whether MDSC subpopulations promote the stemness of colon cancer cells through exosomes secretion, G-MDSCs or M-MDSCs were treated with Small Interfering RNA (siRNA)-Rab27a and co-cultured with CT-26 cells
These results suggest that G-MDSCs and M-MDSCs enhance colon cancer cell stemness in a manner partially dependent on exosomes secretion

Summary

Introduction

CRC patients.[12] Recently, MDSCs identified as a modulator of tumor cell stemness. Colorectal cancer (CRC) is the most common malignant diges- cancer cells by triggering microRNA101 expression in cancer tive tumor. Large-scale efforts to explore the pathogenic mech- cells and subsequently repress the corepressor gene C-terminal anisms and diagnostic molecules associated with this disease binding protein-2 (CtBP2).[13] MDSCs endow stem-like qualineed to be developed.[1] Cancer stem cells (CSCs) are cancer ties to breast cancer cells through IL-6/STAT3 and NO/NOTCH cells that possess characteristics associated with normal stem signaling.[14] the effect of MDSC on CRC cells

Results

Discussion

Conclusion