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Research ArticleExperimental Studies

TU-100 Antagonizes the M2 Polarization Phenotype of Macrophages in the Tumor Microenvironment by Suppressing the TLR4/NF-GraphicB/STAT3 Axis

SHUHAI CHEN, YUJI MORINE, YU SAITO, SHINICHIRO YAMADA, HIROKI TERAOKU, TETSUYA IKEMOTO and MITSUO SHIMADA
Anticancer Research May 2023, 43 (5) 1985-1992; DOI: https://doi.org/10.21873/anticanres.16359
SHUHAI CHEN
Department of Surgery, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
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YUJI MORINE
Department of Surgery, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
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  • For correspondence: ymorine@tokushima-u.ac.jp
YU SAITO
Department of Surgery, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
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SHINICHIRO YAMADA
Department of Surgery, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
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HIROKI TERAOKU
Department of Surgery, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
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TETSUYA IKEMOTO
Department of Surgery, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
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MITSUO SHIMADA
Department of Surgery, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
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Abstract

Background/Aim: Macrophages are the most abundant immune cells in the tumor stroma, and their polarization states within the tumor microenvironment (TME) exert critical roles in tumorigenesis. TU-100 (Daikenchuto) is a commonly prescribed Japanese herbal medicine that has shown anti-cancer effects by regulating cancer-associated fibroblasts (CAFs) in the TME. However, its effects on tumor-associated macrophages (TAMs) remain unclear. Materials and Methods: TAMs were generated by macrophage exposure to tumor-conditioned medium (CM), and their polarization states were evaluated after TU-100 treatment. The underlying mechanism was further studied. Results: TU-100 exhibited little cytotoxicity over a range of doses in M0 macrophages and TAMs. However, it could antagonize the M2-like polarization of macrophages evoked by tumor-CM exposure. These effects might be caused by the inhibition of TLR4/NF-Embedded ImageB/STAT3 signaling in the M2-like phenotype of macrophages. Interestingly, TU-100 antagonized the malignancy promoting effects of M2 macrophages on hepatocellular carcinoma cell lines in vitro. Mechanistically, the administration of TU-100 restrained the high expression of MMP-2, COX-2, and VEGF in TAMs. Conclusion: TU-100 may alleviate the progression of cancer by regulating the M2 polarization of macrophages within the TME, suggesting a viable therapeutic approach.

Key Words:
  • Tumor-associated macrophages
  • M2 polarization
  • tumor microenvironment
  • Toll-like receptor 4
  • nuclear factor-Embedded ImageB
  • Received March 13, 2023.
  • Revision received March 23, 2023.
  • Accepted March 24, 2023.
  • Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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Anticancer Research: 43 (5)
Anticancer Research
Vol. 43, Issue 5
May 2023
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TU-100 Antagonizes the M2 Polarization Phenotype of Macrophages in the Tumor Microenvironment by Suppressing the TLR4/NF-GraphicB/STAT3 Axis
SHUHAI CHEN, YUJI MORINE, YU SAITO, SHINICHIRO YAMADA, HIROKI TERAOKU, TETSUYA IKEMOTO, MITSUO SHIMADA
Anticancer Research May 2023, 43 (5) 1985-1992; DOI: 10.21873/anticanres.16359

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TU-100 Antagonizes the M2 Polarization Phenotype of Macrophages in the Tumor Microenvironment by Suppressing the TLR4/NF-GraphicB/STAT3 Axis
SHUHAI CHEN, YUJI MORINE, YU SAITO, SHINICHIRO YAMADA, HIROKI TERAOKU, TETSUYA IKEMOTO, MITSUO SHIMADA
Anticancer Research May 2023, 43 (5) 1985-1992; DOI: 10.21873/anticanres.16359
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Keywords

  • tumor-associated macrophages
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