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Tytuł:
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Activated HIF1α of tumor cells promotes chemoresistance development via recruiting GDF15-producing tumor-associated macrophages in gastric cancer.
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Autorzy:
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Yu S; Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
Li Q; Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
Yu Y; Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
Cui Y; Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
Li W; Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
Liu T; Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China. .
Liu F; Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China. .
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Źródło:
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Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2020 Oct; Vol. 69 (10), pp. 1973-1987. Date of Electronic Publication: 2020 May 09.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: Berlin : Springer Verlag
Original Publication: Berlin ; New York, NY : Springer International, c1982-
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MeSH Terms:
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Drug Resistance, Neoplasm*
Gene Expression Regulation, Neoplastic*
Biomarkers, Tumor/*metabolism
Growth Differentiation Factor 15/*metabolism
Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
Macrophages/*immunology
Stomach Neoplasms/*pathology
Animals ; Apoptosis ; Biomarkers, Tumor/genetics ; Cell Proliferation ; Female ; Growth Differentiation Factor 15/genetics ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Macrophages/drug effects ; Macrophages/metabolism ; Macrophages/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Nude ; Signal Transduction ; Stomach Neoplasms/drug therapy ; Stomach Neoplasms/immunology ; Stomach Neoplasms/metabolism ; Tumor Cells, Cultured ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/immunology ; Xenograft Model Antitumor Assays
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Grant Information:
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81702965 National Nature Science Foundation of China; 31842033 National Nature Science Foundation of China
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Contributed Indexing:
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Keywords: Chemoresistance; GDF15; Gastric cancer; HIF1α; HMGB1; Tumor-associated macrophages
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Substance Nomenclature:
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0 (Biomarkers, Tumor)
0 (GDF15 protein, human)
0 (Growth Differentiation Factor 15)
0 (HIF1A protein, human)
0 (Hypoxia-Inducible Factor 1, alpha Subunit)
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Entry Date(s):
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Date Created: 20200511 Date Completed: 20201006 Latest Revision: 20201006
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Update Code:
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20240105
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DOI:
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10.1007/s00262-020-02598-5
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PMID:
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32388677
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Chemotherapy is the preferred treatment for advanced stage gastric cancer (GC) patients, and developing chemoresistance is a tremendous challenge to efficacy of GC treatment. The treatments of anti-tumor chemo-agents recruit more tumor-associated macrophages (TAMs) which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we demonstrate that hypoxia-inducible factor 1α (HIF1α) in GC cells is activated upon 5-fluorouracil (5-FU) treatment and results in much more accumulation of M2-type TAMs which protect tumor cells from chemo-agents. Mechanistically, in the GC cells under the 5-FU treatment, reactive oxygen species is accumulated and then induces the activation of HIF1α signaling to drive the expression of high-mobility group box 1, which leads to more macrophage's infiltration into GC tumor. In turn, the recruited TAMs exhibit tumor-protected M2-type phenotype and promote the chemoresistance of GC cells via producing growth differentiation factor 15 (GDF15) to exacerbate the fatty acid β-oxidation in tumor cells. Blocking GDF15 using antibody or inhibiting FAO of tumor cells by etomoxir efficiently gave rise to the tumor cell sensitivity to 5-FU. Therefore, our study demonstrates a novel insight in understanding the cross talking between tumor cells and immune microenvironment and provides new therapeutic targets for clinic treatments of gastric cancer.