C/EBP-δ positively regulates MDSC expansion and endothelial VEGFR2 expression in tumor development
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Yongfen Min1,*, Jingdong Li2,3,*, Peng Qu1 and P. Charles Lin1
1Center for Cancer Research, National Cancer Institutes, Frederick, MD 21702, USA
2Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637007, Sichuan, China
3Hepatobiliary, Pancreatic and Intestinal Diseases Research Institute, North Sichuan Medical College, Nanchong 637007, Sichuan, China
*These authors contributed equally to this work
P. Charles Lin, email: firstname.lastname@example.org
Keywords: MDSCs, C/EBP-δ, VEGFR2, angiogenesis, cancer
Received: November 18, 2016 Accepted: February 12, 2017 Published: March 21, 2017
Vascular endothelial cells and Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs) are two important components that constitute the tumor microenvironment. Targeting these cells offers the potential to halt tumor growth. In this study, we report a common mediator in C/EBP-δ that regulates both components and aids in tumor development. C/EBP-δ is elevated in tumor derived MDSCs. Interestingly, genetic deletion of C/EBP-δ in mice significantly impaired MDSC expansion in response to tumor progression, but it had no effect on Gr-1+CD11b+ cell production in normal development. It suggests a specific role of C/EBP-δ in emergency myelopoiesis under tumor conditions. Consistent with the pro tumor functions of MDSCs, loss of C/EBP-δ resulted in reduced tumor angiogenesis and tumor growth. Moreover, we found expression of C/EBP-δ in vascular endothelial cells. C/EBP-δ regulated cell motility, endothelial network formation and vascular sprouting. Notably, inactivation of C/EBP-δ in endothelial cells specifically inhibited the expression of VEGFR2 but not VEGFR1. Ectopic expression of C/EBP-δ increased and knockdown of the gene decreased VEGFR2 expression. C/EBP-δ is recruited to the promoter region of VEGFR2, indicative of transcriptional regulation. Collectively, this study has identified a positive mediator in C/EBP-δ, which regulates tumor induced MDSC expansion and VEGFR2 expression in endothelium. Considering the importance of MDSCs and endothelial cells in tumor progression, targeting C/EBP-δ may provide an interesting means for cancer therapy, killing two birds with one stone.
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