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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-12142012-144124 |
| Date | 14 December 2012 |
| Creators | Mackert, John Rodway |
| Contributors | Steve Hann, Jin Chen, Bill Tansey, Linda Sealy, Charles Lin |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-12142012-144124/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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