Inhibition of CCL7 derived from Mo-MDSCs prevents metastatic progression from latency in colorectal cancer.
Inhibition of CCL7 derived from Mo-MDSCs prevents metastatic progression from latency in colorectal cancer.
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抑制源自 Mo-MDSC 的 CCL7 可防止结直肠癌潜伏期的转移进展。
DOI：
10.1038/s41419-021-03698-5
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发表时间：
2021-05-13
影响因子：
9
通讯作者：
Liang L
中科院分区：
文献类型：
--
作者：
Ren X;Xiao J;Zhang W;Wang F;Yan Y;Wu X;Zeng Z;He Y;Yang W;Liao W;Ding Y;Liang L
在结直肠癌（CRC）中，明显的转移通常在潜伏数年后出现。但是，导致微转移细胞保持惰性，从而使它们能够长时间存活的信号尚不清楚。免疫荧光和免疫共沉淀法用于探索CCL 7和CCR 2的共定位。采用免疫组织化学（IHC）方法检测小鼠肝转移HT 29细胞的特性。进行流式细胞术测定以检测免疫细胞。Bruberin vivo MS FX Pro Imager观察小鼠结直肠癌肝转移情况。采用实时荧光定量PCR（qRT-PCR）和western blot检测相关蛋白的表达。采用微量RNA测序技术对小鼠结直肠癌组织中micro-M和macro-M的MDSCs差异表达基因进行鉴定。本研究首先建立了大肠癌体外休眠细胞模型和转移性休眠动物模型。结果发现，从大肠癌肝微转移到巨转移，骨髓源性抑制细胞（MDSCs）明显增多。此外，与多形核MDSC（PMN-MDSC）相比，单核MDSC（Mo-MDSC）显著促进微转移细胞的休眠激活。Mo-MDSC分泌的CCL 7与微转移细胞的膜蛋白CCR 2结合，然后刺激JAK/STAT 3通路以激活休眠细胞。低剂量CCL 7和MDSCs抑制剂体内给药可显著维持结直肠癌转移细胞长时间的休眠状态，减少根治术后的转移或复发。临床上，CCR患者血中CCL 7水平与Mo-MDSCs数量呈正相关，并与近期复发和远处转移密切相关。Mo-MDSC分泌的CCL 7在启动转移性潜伏CRC细胞的生长中起重要作用。抑制CCL 7可能为预防转移复发提供潜在的治疗策略。
In colorectal cancer (CRC), overt metastases often appear after years of latency. But the signals that cause micro-metastatic cells to remain indolent, thereby enabling them to survive for extended periods of time, are unclear. Immunofluorescence and co-immunoprecipitation assays were used to explore the co-localization of CCL7 and CCR2. Immunohistochemical (IHC) assays were employed to detect the characters of metastatic HT29 cells in mice liver. Flow cytometry assays were performed to detect the immune cells. Bruberin vivo MS FX Pro Imager was used to observe the liver metastasis of CRC in mice. Quantitative real-time PCR (qRT-PCR) and western blot were employed to detect the expressions of related proteins. Trace RNA sequencing was employed to identify differentially expressed genes in MDSCs from liver micro-M and macro-M of CRC in mice. Here, we firstly constructed the vitro dormant cell models and metastatic dormant animal models of colorectal cancer. Then we found that myeloid-derived suppressor cells (MDSCs) were increased significantly from liver micro-metastases to macro-metastases of CRC in mice. Moreover, monocytic MDSCs (Mo-MDSC) significantly promoted the dormant activation of micro-metastatic cells compared to polymorphonuclear MDSCs (PMN-MDSC). Mechanistically, CCL7 secreted by Mo-MDSCs bound with membrane protein CCR2 of micro-metastatic cells and then stimulated the JAK/STAT3 pathway to activate the dormant cells. Low-dose administration of CCL7 and MDSCs inhibitors in vivo could significantly maintain the CRC metastatic cells dormant status for a long time to reduce metastasis or recurrence after radical operation. Clinically, the level of CCL7 in blood was positively related to the number of Mo-MDSCs in CCR patients, and highly linked with the short-time recurrence and distant metastasis. CCL7 secreted by Mo-MDSCs plays an important role in initiating the outgrowth of metastatic latent CRC cells. Inhibition of CCL7 might provide a potential therapeutic strategy for the prevention of metastasis recurrence.
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影响因子：
10.1
作者：
Gabrilovich DI
通讯作者：
Gabrilovich DI
癌细胞休眠：癌症复发和转移的机制和影响
影响因子：
4
作者：
Gao XL;Zhang M;Tang YL;Liang XH
通讯作者：
Liang XH
影响因子：
3.7
作者：
Li S;Kennedy M;Payne S;Kennedy K;Seewaldt VL;Pizzo SV;Bachelder RE
通讯作者：
Bachelder RE
影响因子：
6.6
作者：
Angell, Trevor E.;Lechner, Melissa G.;Epstein, Alan L.
通讯作者：
Epstein, Alan L.
影响因子：
5.8
作者：
Jordan, Kimberly R.;Amaria, Rodabe N.;Ramirez, Oscar;Callihan, Eryn B.;Gao, Dexiang;Borakove, Michelle;Manthey, Elizabeth;Borges, Virginia F.;McCarter, Martin D.
通讯作者：
McCarter, Martin D.