Prostaglandin E2 produced by myeloid-derived suppressive cells induces cancer stem cells in uterine cervical cancer

Abstract

// Hiromasa Kuroda 1, * , Seiji Mabuchi 1, * , Eriko Yokoi 1, * , Naoko Komura 1 , Katsumi Kozasa 1 , Yuri Matsumoto 1 , Mahiru Kawano 1 , Ryoko Takahashi 1 , Tomoyuki Sasano 1 , Kotaro Shimura 1 , Michiko Kodama 1 , Kae Hashimoto 1 , Kenjiro Sawada 1 , Eiichi Morii 2 and Tadashi Kimura 1 1 Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan 2 Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan * These authors contributed equally to this work Correspondence to: Seiji Mabuchi, email: smabuchi@gyne.med.osaka-u.ac.jp Keywords: MDSC; CSC; prostaglandin E2; cervical cancer; celecoxib Received: April 13, 2018      Accepted: October 24, 2018      Published: November 20, 2018 ABSTRACT Myeloid-derived suppressor cells (MDSCs) enhance tumor progression by suppressing tumor-specific T cell responses, stimulating tumor angiogenesis, or promoting tumor cell metastasis. However, the biology of MDSCs have not been fully investigated. In the current study, we investigated the role of MDSCs in inducing cancer stem-like cells and explored a clinically feasible approach for targeting MDSCs-mediated cancer stem-like cells induction. In vitro and in vivo experiments revealed that MDSCs induced by tumor-derived G-CSF enhanced the stemness of cervical cancer cells by producing Prostaglandin E2 (PGE2). We also demonstrated that anti-Gr-1 neutralizing antibody or celecoxib inhibited the induction of cancer stem-like cells and enhanced the efficacy of cisplatin in cervical cancer. In clinical samples, MDSCs, PGE2, and CSCs had positive correlations. In conclusion, G-CSF-induced MDSCs enhance the stemness of uterine cervical cancer cells by producing PGE2. Targeting MDSCs or PGE2 might be a reasonable strategy for enhancing the efficacies of treatments.