Tumor-Secreted GRP78 Promotes the Establishment of a Pre-metastatic Niche in the Liver Microenvironment.
Tumor-Secreted GRP78 Promotes the Establishment of a Pre-metastatic Niche in the Liver Microenvironment.
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肿瘤分泌的 GRP78 促进肝脏微环境中转移前生态位的建立
DOI：
10.3389/fimmu.2020.584458
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发表时间：
2020
影响因子：
7.3
通讯作者：
Shen G
中科院分区：
文献类型：
--
作者：
Chen L;Zheng H;Yu X;Liu L;Li H;Zhu H;Zhang Z;Lei P;Shen G
肝脏是一个免疫耐受器官，也是各种癌症远处转移的常见部位。葡萄糖调节蛋白78（GRP 78）的表达水平与肿瘤的恶性程度有关。从肿瘤细胞释放的分泌型GRP 78（sGRP 78）通过调节巨噬细胞和树突状细胞（DC）中的细胞因子产生而有助于建立免疫抑制性肿瘤微环境。然而，sGRP 78在肝中肿瘤细胞定植和转移中的作用仍不清楚。在此，我们发现，与其他组织和器官相比，GRP 78在肝脏中以更高的水平表达。我们使用sGRP 78过表达的乳腺癌细胞系（E0771）进行活体成像，发现sGRP 78与肝脏中的树突状细胞（DC）和F4/80+巨噬细胞相互作用。重要的是，sGRP 78过表达抑制DC活化并诱导F4/80+巨噬细胞中的M2样极化。此外，sGRP 78过表达增强了肝脏中TGF-β的产生。总之，sGRP 78通过重塑肿瘤微环境和促进免疫耐受来促进肿瘤细胞在肝脏中的定植。应进一步检查sGRP 78靶向策略预防或治疗肝转移的能力。
The liver is an immunologically tolerant organ and a common site of distant metastasis for various cancers. The expression levels of glucose-regulated protein 78 (GRP78) have been associated with tumor malignancy. Secretory GRP78 (sGRP78) released from tumor cells contributes to the establishment of an immunosuppressive tumor microenvironment by regulating cytokine production in macrophages and dendritic cells (DCs). However, the role of sGRP78 on tumor cell colonization and metastasis in the liver remains unclear. Herein, we found that GRP78 was expressed at higher levels in the liver compared to other tissues and organs. We performed intravital imaging using a sGRP78-overexpressing breast cancer cell line (E0771) and found that sGRP78 interacted with dendritic cells (DCs) and F4/80+ macrophages in the liver. Importantly, sGRP78 overexpression inhibited DC activation and induced M2-like polarization in F4/80+ macrophages. Moreover, sGRP78 overexpression enhanced TGF-β production in the liver. In conclusion, sGRP78 promotes tumor cell colonization in the liver by remodeling the tumor microenvironment and promoting immune tolerance. The ability of sGRP78-targeting strategies to prevent or treat liver metastasis should be further examined.