Inhibition of vacuolar ATPase subunit in tumor cells delays tumor growth by decreasing the essential macrophage population in the tumor microenvironment
Inhibition of vacuolar ATPase subunit in tumor cells delays tumor growth by decreasing the essential macrophage population in the tumor microenvironment
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DOI：
10.1038/onc.2015.159
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发表时间：
2016-02-25
期刊：
影响因子：
8
通讯作者：
Beaman, K. D.
中科院分区：
文献类型：
--
作者：
Katara, G. K.;Kulshrestha, A.;Beaman, K. D.
在癌细胞中，空泡atp酶（v - atp酶）是一种多亚基酶，在血浆和囊泡膜上表达，并对转移行为产生关键影响。V-ATPase a2亚型的可溶性、断裂的n端结构域与巨噬细胞体外诱导的致瘤性特征有关。在小鼠4T-1乳腺癌模型中，我们通过抑制肿瘤细胞中的a2亚型（a2V）进一步研究了其在肿瘤进展中的体内作用以及对肿瘤微环境的伴随作用。结果表明，与对照4T-1细胞相比，与a2V敲低（sh-a2） 4T-1细胞共培养的巨噬细胞在体外产生更少的致瘤因子，抑制t细胞活化和增殖的能力降低。数据分析显示，与对照组相比，接种sh-a2 4T-1细胞的Balb/c小鼠乳腺肿瘤生长延迟。sh-a2肿瘤中纯化的CD11b（+）巨噬细胞显示甘露糖受体-1 （CD206）、白细胞介素-10、转化生长因子- β、精氨酸酶-1、基质金属蛋白酶和血管内皮生长因子的表达降低。流式细胞术分析肿瘤浸润的巨噬细胞显示，与对照组相比，sh-a2肿瘤中F4/80(+) CD11c(+) CD206（+）巨噬细胞数量明显减少。在sh-a2肿瘤中，大多数巨噬细胞为F4/80(+) CD11c(+)（抗肿瘤M1巨噬细胞），提示它是肿瘤生长延迟的原因。此外，与对照组相比，来自sh-a2肿瘤的肿瘤浸润性巨噬细胞的CD206表达降低，而CD11c表达不受影响。这些发现表明，在肿瘤细胞中缺乏a2V的情况下，肿瘤微环境中的巨噬细胞群会发生改变，从而影响体内肿瘤的生长。我们认为，通过参与宿主免疫系统，可以通过a2V靶向肿瘤细胞来控制肿瘤的生长。
In cancer cells, vacuolar ATPase (V-ATPase), a multi-subunit enzyme, is expressed on the plasma as well as vesicular membranes and critically influences metastatic behavior. The soluble, cleaved N-terminal domain of V-ATPase a2 isoform is associated with in vitro induction of tumorigenic characteristics in macrophages. This activity led us to further investigate its in vivo role in cancer progression by inhibition of a2 isoform (a2V) in tumor cells and the concomitant effect on tumor microenvironment in the mouse 4T-1 breast cancer model. Results showed that macrophages cocultivated with a2V knockdown (sh-a2) 4T-1 cells produce lower amounts of tumorigenic factors in vitro and have reduced ability to suppress T-cell activation and proliferation compared with control 4T-1 cells. Data analysis showed a delayed mammary tumor growth in Balb/c mice inoculated with sh-a2 4T-1 cells compared with control. The purified CD11b(+) macrophages from sh-a2 tumors showed a reduced expression of mannose receptor-1 (CD206), interleukin-10, transforming growth factor-beta, arginase-1, matrix metalloproteinase and vascular endothelial growth factor. Flow cytometric analysis of tumor-infiltrated macrophages showed a significantly low number of F4/80(+) CD11c(+) CD206(+) macrophages in sh-a2 tumors compared with control. In sh-a2 tumors, most of the macrophages were F4/80(+) CD11c(+) (antitumor M1 macrophages) suggesting it to be the reason behind delayed tumor growth. Additionally, tumor-infiltrating macrophages from sh-a2 tumors showed a reduced expression of CD206 compared with control whereas CD11c expression was unaffected. These findings demonstrate that in the absence of a2V in tumor cells, the resident macrophage population in the tumor microenvironment is altered which affects in vivo tumor growth. We suggest that by involving the host immune system, tumor growth can be controlled through targeting of a2V on tumor cells.