Abstract
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.
Highlights
Tumor metastasis remains the major cause of cancer-related deaths
MCherry primarily localized in the cytoplasm in E0771-mCherry-Secretory GRP78 (sGRP78) cells, it was evenly distributed in E0771-mCherry cells (Figure 1A)
We found no difference in the levels of dendritic cells (DCs) recruitment, the expression levels of MHC-II on DCs was significantly lower in the E0771-mCherry-sGRP78 group compared with control mice (P < 0.05; Figures 2B,C). sGRP78 did not affect the expression of CD86 or MHC-II on liver sinusoidal endothelial cells (LSECs) (Figures 2D,E)
Summary
Tumor metastasis remains the major cause of cancer-related deaths. The liver represents a common site of distant metastasis for various cancers, including melanoma, breast cancer, and colorectal cancer. The successful colonization of distant organs by circulating tumor cells (CTCs) is key for cancer metastasis [1], and the local microenvironment of these organs plays decisive roles in this process. Prior to cancer cell dissemination, the primary tumor secretes cytokines and vesicles, which create a pre-metastatic niche in secondary organs and metastatic sites. Myeloid-derived suppressor cells (MDSCs) and other immune-suppressive cells and secreted factors are essential for the establishment of the pre-metastatic niche. Upon establishment of a pre-metastatic niche, Tumor-Secreted GRP78, Liver Pro-metastatic Niche
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