Dataset Information

Tumor-Secreted GRP78 Promotes the Establishment of a Pre-metastatic Niche in the Liver Microenvironment.

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-? 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.

SUBMITTER: Chen L

PROVIDER: S-EPMC7550426 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tumor-Secreted GRP78 Promotes the Establishment of a Pre-metastatic Niche in the Liver Microenvironment.

Chen Lu L Zheng Hao H Yu Xiang X Liu Lei L Li Heli H Zhu Huifen H Zhang Zhihong Z Lei Ping P Shen Guanxin G

Frontiers in immunology 20200929

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 li ...[more]

PMID: 33133103

Similar Datasets

Project description:Tumor-associated macrophages (TAMs) play an essential role in metastasis. However, what enables TAMs to have a superior capacity to establish pre-metastatic microenvironment in distant organs is unclear. Here we have begun to uncover the effects of cytochrome P450 (CYP) 4A in TAMs on lung pre-metastatic niche formation and metastasis. CYP4A+ TAM infiltration was positively associated with metastasis, pre-metastatic niche formation and poor prognosis in breast cancer patients. The pharmacological inhibition of CYP4A reduced lung pre-metastatic niche formation (evidenced by a decrease in vascular endothelial growth factor receptor 1 positive (VEGFR1+) myeloid cell recruitment and pro-metastatic protein expression) and metastatic burden, accompanied with TAM polarization away from the M2 phenotype in spontaneous metastasis models of 4T1 breast cancer and B16F10 melanoma. Co-implantation of 4T1 cells with CYP4A10high macrophages promoted lung pre-metastatic niche formation and metastasis. Depletion of TAMs disrupted lung pre-metastatic niches and thereby prevented metastasis. Treatment with the CM from CYP4A10high M2 macrophages (M2) increased pre-metastatic niche formation and metastatic burden in the lungs, whereas CYP4A inhibition attenuated these effects. In vitro TAM polarization away from the M2 phenotype induced by CYP4A inhibition decreased VEGFR1+ myeloid cell migration and fibronectin expression, accompanied with downregulation of STAT3 signaling. Conversely, overexpression of CYP4A or exogenous addition of 20-hydroxyeicosatetraenoic acid promoted M2 polarization and cytokine production of macrophages and thereby enhanced migration of VEGFR1+ myeloid cells, which were reversed by siRNA or pharmacological inhibition of STAT3. Importantly, a combined blocking M2 macrophage-derived factors TGF-?, VEGF and SDF-1 abolished VEGFR1+ myeloid cell migration and fibroblast activation induced by CYP4A. In summary, CYP4A in TAMs is crucial for lung pre-metastatic niche formation and metastasis, and may serve as a potential therapeutic target in human cancer.

Dataset Information

Tumor-Secreted GRP78 Promotes the Establishment of a Pre-metastatic Niche in the Liver Microenvironment.

Publications

Tumor-Secreted GRP78 Promotes the Establishment of a Pre-metastatic Niche in the Liver Microenvironment.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets