Bone marrow cells are differentiated into MDSCs by BCC-Ex through down-regulating the expression of CXCR4 and activating STAT3 signalling pathway.

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Tytuł:: Bone marrow cells are differentiated into MDSCs by BCC-Ex through down-regulating the expression of CXCR4 and activating STAT3 signalling pathway.
Autorzy:: Liu QW; The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China.
Chen Y; The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China.
Li JY; School of Chemistry, Biology and Material Science, East China University of Technology, Nanchang, China.
Xiao L; The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China.
Zhang WJ; The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China.
Zhao JL; The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China.
Gu HC; The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China.; School of Life and Science, Nanchang University, Nanchang, China.
Wu HY; The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China.
Zuo GS; The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China.
Deng KY; The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China.; School of Life and Science, Nanchang University, Nanchang, China.
Xin HB; The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China.; School of Life and Science, Nanchang University, Nanchang, China.
Źródło:: Journal of cellular and molecular medicine [J Cell Mol Med] 2021 Jun; Vol. 25 (12), pp. 5497-5510. Date of Electronic Publication: 2021 May 06.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: Oxford, England : Wiley-Blackwell
Original Publication: Bucharest : "Carol Davila" University Press, 2000-
MeSH Terms:: Bone Marrow Cells/*pathology
Breast Neoplasms/*pathology
Exosomes/*metabolism
Myeloid-Derived Suppressor Cells/*pathology
Nitric Oxide Synthase Type II/*metabolism
Receptors, CXCR4/*antagonists & inhibitors
STAT3 Transcription Factor/*metabolism
Animals ; Bone Marrow Cells/immunology ; Bone Marrow Cells/metabolism ; Breast Neoplasms/genetics ; Breast Neoplasms/immunology ; Breast Neoplasms/metabolism ; Cell Differentiation ; Female ; Humans ; Mice ; Mice, Inbred BALB C ; Myeloid-Derived Suppressor Cells/immunology ; Myeloid-Derived Suppressor Cells/metabolism ; Nitric Oxide Synthase Type II/genetics ; Receptors, CXCR4/genetics ; Receptors, CXCR4/metabolism ; STAT3 Transcription Factor/genetics ; Signal Transduction ; T-Lymphocytes/immunology ; Tumor Microenvironment
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Grant Information:: 81873659 National Natural Science Foundation of China; 81970256 National Natural Science Foundation of China; 81760118 National Natural Science Foundation of China; 81760140 National Natural Science Foundation of China; 91639106 National Natural Science Foundation of China; 2015202004 Jiangxi Provincial Collaborative Innovation Center of Biopharmaceutics and Biotechnology; 2018ACB21043 Jiangxi Provincial Department of Science and Technology of China; 20192BAB205032 Jiangxi Provincial Department of Science and Technology of China
Contributed Indexing:: Keywords: CXCR4; MDSCs; STAT3; breast cancer; exosomes
Substance Nomenclature:: 0 (CXCR4 protein, human)
0 (Receptors, CXCR4)
0 (STAT3 Transcription Factor)
0 (STAT3 protein, human)
EC 1.14.13.39 (NOS2 protein, human)
EC 1.14.13.39 (Nitric Oxide Synthase Type II)
Entry Date(s):: Date Created: 20210506 Date Completed: 20211001 Latest Revision: 20211001
Update Code:: 20240104
PubMed Central ID:: PMC8184685
DOI:: 10.1111/jcmm.16559
PMID:: 33955151
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Studies showed that the increase of myeloid-derived suppressor cells (MDSCs) in tumour microenvironment is closely related to the resistant treatment and poor prognosis of metastatic breast cancer. However, the effect of tumour-derived exosomes on MDSCs and its mechanism are not clear. Here, we reported that breast cancer cells (4T1)-secreted exosomes (BCC-Ex) were able to differentiate bone marrow cells into MDSCs and significantly inhibited the proliferation of T lymphocytes to provide an immunosuppressive microenvironment for cancer cells in vivo and in vitro. The number of MDSCs in bone marrow and spleen of 4T1 tumour-bearing mice and BCC-Ex infused mice was significantly higher than that of normal mice, whereas the number of T lymphocytes in spleen was significantly decreased. In addition, BCC-Ex markedly promoted the differentiation of MDSCs from bone marrow cells or bone marrow cells derived macrophages, seen as the increased expressions of MDSCs-related functional proteins Arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS). Furthermore, BCC-Ex significantly down-regulated the expressions of chemokine receptor CXCR4 and markedly up-regulated the levels of inflammatory cytokines IL-6 and IL-10 in bone marrow cells and macrophages and remarkably inhibited the division and proliferation of T cells. Importantly, CXCR4 agonist, CXCL12, could reverse the function of BCC-Ex, indicating that BCC-Ex-induced MDSCs might be dependent on the down-regulation of CXCR4. Western blot showed that BCC-Ex significantly promoted the phosphorylation of STAT3 in bone marrow cells, resulting in the inhibitions of the proliferation and apoptosis of bone marrow cells, and the aggravation of the differentiation of bone marrow cells into MDSCs.
(© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

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