Dual negative roles of C/EBPα in the expansion and pro-tumor functions of MDSCs.
Dual negative roles of C/EBPα in the expansion and pro-tumor functions of MDSCs.
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DOI：
10.1038/s41598-017-12968-2
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发表时间：
2017-10-25
影响因子：
4.6
通讯作者：
Lin PC
中科院分区：
文献类型：
--
作者：
Mackert JR;Qu P;Min Y;Johnson PF;Yang L;Lin PC
骨髓源性抑制细胞（MDSC）在癌症患者和荷瘤小鼠体内大幅扩增。它们渗透到肿瘤并调节肿瘤微环境。为了鉴定负责 MDSC 扩增和肿瘤促进功能的分子介质，我们发现与非肿瘤宿主相比，荷瘤小鼠的 MDSC 中 CCAAT/增强子结合蛋白 α (C/EBPα) 表达显着降低。肿瘤条件培养基下调 C/EBPα 表达，表明肿瘤分泌因子抑制基因表达。与 C/EBPα 调节造血祖细胞增殖和生长停滞之间平衡的功能一致，C/EBPα 的骨髓谱系特异性缺失导致 MDSC 增殖和扩增显着增强，以及骨髓祖细胞的增加和成熟细胞的减少。此外，MDSC 中 C/EBPα 的缺失通过上调 iNOS 和精氨酸酶以及 MMP-9 和 VEGF 的产生，增强了这些细胞的促血管生成、免疫抑制和促肿瘤发生行为。因此，在 C/EBPα 条件缺失小鼠中生长的肿瘤表现出更大的 MDSC 浸润、增加的血管化和加速的肿瘤生长。综上所述，本研究揭示了 C/EBPα 在 MDSC 扩张以及促血管生成和免疫抑制功能中的双重负面作用。
Myeloid-derived suppressor cells (MDSCs) are greatly expanded in cancer patients and tumor-bearing mice. They infiltrate into tumors and modulate the tumor microenvironment. In an effort to identify molecular mediators responsible for expansion and the tumor-promoting function of MDSCs, we discovered CCAAT/enhancer binding protein alpha (C/EBPα) expression was significantly reduced in MDSCs from tumor-bearing mice compared to non-tumor-bearing hosts. Tumor-conditioned medium down-regulated C/EBPα expression, suggesting tumor secreted factors inhibiting the gene expression. Consistent with the function of C/EBPα in regulating the balance between proliferation and growth arrest in hematopoietic progenitors, myeloid lineage specific deletion of C/EBPα resulted in significantly enhanced MDSC proliferation and expansion, as well as an increase of myeloid progenitors and a decrease of mature cells. In addition, deletion of C/EBPα in MDSCs enhanced the pro-angiogenic, immune suppressive and pro-tumorigenic behavior of these cells by upregulating the production of iNOS and arginase, as well as MMP-9 and VEGF. Accordingly, tumors growing in C/EBPα conditional null mice displayed greater MDSC infiltration, increased vascularization and accelerated tumor growth. Taken together, this study reveals dual negative roles of C/EBPα in the expansion as well as pro-angiogenic and immune suppressive functions in MDSCs.
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DOI：
10.1084/jem.20050067
发表时间：
2005-07-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Porse BT;Bryder D;Theilgaard-Mönch K;Hasemann MS;Anderson K;Damgaard I;Jacobsen SE;Nerlov C
通讯作者：
Nerlov C
影响因子：
4.4
作者：
Stewart, Trina J.;Liewehr, David J.;Abrams, Scott I.
通讯作者：
Abrams, Scott I.
影响因子：
50.3
作者：
Yang, Li;Huang, Jianhua;Mosesl, Harold L.
通讯作者：
Mosesl, Harold L.
DOI：
10.1111/j.1432-1033.1994.tb20045.x
发表时间：
1994-11-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
BONIFER, C;BOSCH, FX;SIPPEL, AE
通讯作者：
SIPPEL, AE
影响因子：
5.3
作者：
Lee, YH;Sauer, B;Gonzalez, FJ
通讯作者：
Gonzalez, FJ