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Erschienen in: Cancer Immunology, Immunotherapy 10/2020

09.05.2020 | Original Article

Activated HIF1α of tumor cells promotes chemoresistance development via recruiting GDF15-producing tumor-associated macrophages in gastric cancer

verfasst von: Shan Yu, Qian Li, Yiyi Yu, Yuehong Cui, Wei Li, Tianshu Liu, Fenglin Liu

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 10/2020

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Abstract

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.
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Metadaten
Titel
Activated HIF1α of tumor cells promotes chemoresistance development via recruiting GDF15-producing tumor-associated macrophages in gastric cancer
verfasst von
Shan Yu
Qian Li
Yiyi Yu
Yuehong Cui
Wei Li
Tianshu Liu
Fenglin Liu
Publikationsdatum
09.05.2020
Verlag
Springer Berlin Heidelberg
Erschienen in
Cancer Immunology, Immunotherapy / Ausgabe 10/2020
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-020-02598-5

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