MiR-26b-5p in small extracellular vesicles derived from dying tumor cells after irradiation enhances the metastasis promoting microenvironment in esophageal squamous cell carcinoma
MiR-26b-5p in small extracellular vesicles derived from dying tumor cells after irradiation enhances the metastasis promoting microenvironment in esophageal squamous cell carcinoma
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辐射后死亡肿瘤细胞衍生的小细胞外囊泡中的 MiR-26b-5p 增强食管鳞状细胞癌中促进转移的微环境
DOI：
10.1016/j.canlet.2022.215746
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发表时间：
2022-05-25
期刊：
影响因子：
9.7
通讯作者：
Li，Baosheng
中科院分区：
文献类型：
--
作者：
Yin，Xiaoyang;Tian，Meng;Li，Baosheng
放射治疗在食管鳞状细胞癌局部控制方面是有效的，然而，放射引起的肿瘤微环境的变化也会促进转移。垂死的肿瘤细胞在促进活肿瘤细胞的存活方面起着至关重要的作用;然而，很少有研究调查垂死的肿瘤细胞对肿瘤微环境的影响。由于骨髓来源的抑制细胞（MDSC）和巨噬细胞构成了转移前小生境（PMN），我们使用4-硝基喹啉-1-氧化物诱导的原位肿瘤模型来研究辐射对食管鳞状细胞癌（ESCC）中MDSC和巨噬细胞的影响。当原发肿瘤部位被照射时，我们观察到脾脏中MDSC的增加以及肺和肝脏中PMN成分的沉积。增强MDSC的积累和功能诱导的小细胞外囊泡（sEV）从辐射荷瘤小鼠分离。使用来源于ESCC细胞系的sEV再次确认照射后sEV的MDSC诱导功能。辐射诱导的sEV中miR-26 b-5 p上调通过靶向磷酸酶和张力蛋白同源物增强MDSC扩增和活化。我们的研究结果首次阐明了一种机制，即死亡的肿瘤细胞增强沉积的中性粒细胞成分和增强MDSC在ESCC照射后。sEVs在介导原发肿瘤与微环境之间的信号以形成辐射后促进转移的微环境中起重要作用。此外，miR-26 b-5 p或PI 3 K/AKT信号通路抑制剂应在临床试验中与放疗联合评估，作为改善结局的策略。
Radiation therapy is effective in achieving local control in esophageal squamous cell carcinoma; however, changes in the tumor microenvironment induced by radiation can also promote metastasis. Dying tumor cells play vital roles in promoting the survival of living tumor cells; however, few studies have investigated the effects of dying tumor cells on the tumor microenvironment. Since myeloid-derived suppressor cells (MDSCs) and macrophages constitute the pre-metastatic niche (PMN), we used a 4-nitroquinoline-1-oxide inducedin situtumor model to investigate the effects of irradiation on MDSCs and macrophages in esophageal squamous cell carcinoma (ESCC). When primary tumor sites were irradiated, we observed an increase in MDSCs in the spleen and the deposition of PMN components in lung and liver. Enhanced MDSC accumulation and function were induced by small extracellular vesicles (sEVs) isolated from irradiated tumor-bearing mice. The MDSC induction function of sEVs after irradiation was reaffirmed using sEVs derived from ESCC cell lines. The irradiation-induced upregulation of miR-26b-5p in sEVs enhanced MDSC expansion and activation by targeting phosphatase and tensin homolog. Our results first elucidated a mechanism by which dying tumor cells enhanced the deposition of PMN components and potentiated MDSCs in ESCC after irradiation. sEVs played a vital role in mediating signals between the primary tumor and the microenvironment to form a metastasis-promoting microenvironment after irradiation. Furthermore, miR-26b-5p or PI3K/AKT signaling pathway inhibitors should be evaluated in clinical trials in combination with radiotherapy as a strategy to improve outcomes.