逍遥散通过调节肿瘤免疫微环境抑制肺转移前微环境形成  

XiaoYaoSan inhibits lung pre-metastatic niche formation through tumor immune microenvironment regulation

作　　者：汤晓霞 邓皖利[1] 张勇[1] 陈彬[1] 柴妮 张澍 谢曼丽 TANG Xiaoxia;DENG Wanli;ZHANG Yong;CHEN Bin;CHAI Ni;ZHANG Shu;XIE Manli(Putuo Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai 200062,China;Yueyang Hospital of Integrated Traditional Chinese and Western Medicine,Shanghai University of Traditional Chinese Medicine;Changzheng Town Community Health Service Center,Putuo District)

机构地区：[1]上海中医药大学附属普陀医院,200062 [2]上海中医药大学附属岳阳中西医结合医院 [3]上海市普陀区长征镇社区卫生服务中心

出　　处：《天津医药》2023年第3期263-268,共6页Tianjin Medical Journal

基　　金：上海市普陀区卫生健康系统科技创新项目(Ptkwws201907,Ptkwws202002);上海市科学技术委员会科研计划项目(19401933800,21010504300)。

摘　　要：目的探讨逍遥散抗肿瘤转移作用的机制。方法建立小鼠结肠癌CT26.WT移植瘤及肺转移模型,通过活体成像、肺组织解剖以及HE染色评价不同剂量(200、400、800 mg)逍遥散干预下的肺转移情况。免疫荧光及Western blot检测肿瘤M2型巨噬细胞标志物CD206、ARG1、PDL2表达;酶联免疫吸附试验检测血清中转化生长因子(TGF)-β和肿瘤坏死因子(TNF)-α的水平;流式细胞术检测肺组织中血管内皮生长因子受体1阳性(VEGFR1+)髓系细胞的募集情况;Western blot检测原位肿瘤组织磷脂酰肌醇3激酶(STAT3)、血管内皮生长因子(VEGF)及肺组织中转移前微环境标志物基质金属蛋白酶(MMP)-9、S100A8及Fibronectin表达。结果逍遥散干预后,肺转移灶显著减少,小鼠肺组织中MMP-9、S100A8及Fibronectin的表达量显著降低,肿瘤相关巨噬细胞发生M1极化,血清中TGF-β的水平显著降低,TNF-α的水平显著升高,小鼠肺组织中VEGFR1+髓系细胞募集明显减少,肿瘤组织中STAT3磷酸化被抑制,VEGF表达量显著降低。结论逍遥散的抗肿瘤转移活性与其抑制转移前微环境的能力有关,并且这种抑制作用可能通过肿瘤相关巨噬细胞的表型转化以及抑制STAT3信号转导实现。Objective To investigate the mechanism of XiaoYaoSan in anti-tumor metastasis.Methods A mouse model of CT26.WT colon cancer xenograft and lung metastasis was established.In vivo imaging of small animals,lung tissue anatomy and HE staining were performed to evaluate the lung metastasis under different doses(200,400 and 800 mg)of XiaoYaoSan intervention.Tumor M2 macrophage markers were detected by immunofluorescence and Western blot assay.Serum levels of transforming growth factor(TGF)-βand tumor necrosis factor(TNF)-αwere detected by enzyme-linked immunosorbent assay(ELISA).The recruitment of VEGFR1+myeloid cells in lung tissue was detected by flow cytometry.The expression levels of phosphatidylinositol 3-kinase(STAT3),vascular endothelial growth factor(VEGF)and premetastasis microenvironment markers matrix metalloproteinase(MMP)-9,S100A8 and Fibronectin were detected by Western blot assay.Results After XiaoYaoSan intervention,the lung metastasis was significantly reduced,expression levels of MMP-9,S100A8 and Fibronectin in lung tissue were significantly decreased,M1 polarization occurred in tumorassociated macrophages,the serum level of TGF-βwas significantly decreased,and TNF-αlevel was significantly increased.The recruitment of VEGFR1+myeloid cells was significantly decreased in lung tissue,STAT3 phosphorylation was inhibited,and VEGF expression was significantly decreased.Conclusion The antimetastatic activity of XiaoYaoSan is related to its ability to inhibit the pre-metastatic microenvironment,which may be realized by the phenotypic transformation of tumor-associated macrophages and inhibition of STAT3 signal transduction.

关 键 词：逍遥散 肿瘤免疫微环境 转移前微环境 肿瘤相关巨噬细胞 肿瘤转移 

分 类 号：R73-37[医药卫生—肿瘤]