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

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.