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Title page for ETD etd-12142012-144124


Type of Document Dissertation
Author Mackert, John Rodway
Author's Email Address john.r.mackert@gmail.com
URN etd-12142012-144124
Title Dual Negative Roles of C/EBPα in the Expansion and Pro-angiogenic Function of Myeloid-Derived Suppressor Cells
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Steve Hann Committee Chair
Bill Tansey Committee Member
Charles Lin Committee Member
Jin Chen Committee Member
Linda Sealy Committee Member
Keywords
  • MDSCs
  • C/EBPα
  • myeloid-derived suprressor cells
  • angiogenesis
Date of Defense 2011-12-21
Availability unrestricted
Abstract
Myeloid-derived suppressor cells (MDSCs) play an important role in cancer progression. Elucidating the mechanisms involved in the expansion and function of these cells is important in the fight against cancer. A microarray comparing splenic Gr-1+CD11b+ cells from tumor-bearing mice and tumor-free mice revealed C/EBPα expression was reduced more than 4-fold in the tumor-derived cells. Based on this finding and published reports, we hypothesized that tumors induce MDSC production through down-regulation of C/EBPα in myeloid cells.

In Chapter II, the role of C/EBPα as a negative regulator of MDSC expansion was investigated. Deletion of myeloid C/EBPα in mice yielded an increase in myeloid progenitors and a reduction in mature myeloid cells. Upon inoculation with tumor cells, MDSC production was enhanced nearly two-fold in mice lacking myeloid C/EBPα, while myeloid progenitors were reduced, perhaps because more progenitors became MDSCs in the absence of C/EBPα.

In Chapter III, we sought to determine whether C/EBPα is a negative regulator of the immune suppressive and pro-angiogenic properties of MDSCs. When inoculated with tumor cells, MDSC infiltration and tumor vascularization was significantly greater in C/EBPα conditional null mice, resulting in markedly accelerated tumor growth. When MDSCs were injected with tumor cells into mice, C/EBPα ablation resulted in an enhancement in the pro-tumor MDSC phenotype: tumor growth and tumor angiogenesis was significantly greater. We then measured the expression of genes involved in MDSC-mediated immune suppression and angiogenesis and found that C/EBPα deletion resulted in MMP-9, VEGF and iNOS upregulation. Additionally, we observed increased NO production but no difference in arginase expression or immune suppression. Since NO also regulates angiogenesis, we concluded that C/EBPα inhibits the pro-angiogenic but not the immune-suppressive properties of MDSCs.

Our findings reveal dual negative roles for C/EBPα in the expansion and pro-angiogenic gene expression in MDSCs, suggesting that overcoming these functions through C/EBPα inhibition may be a critical step in MDSC maturation. Our work indicates that therapy aimed at restoring C/EBP expression in MDSCs may be a viable weapon in the fight against cancer.

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