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Targeted knock-in mice expressing the oxidase-fixed form of xanthine oxidoreductase favor tumor growth

Author

Listed:
  • Teruo Kusano

    (Nippon Medical School)

  • Driss Ehirchiou

    (University of Lausanne
    University of Lausanne, CHUV)

  • Tomohiro Matsumura

    (Nippon Medical School
    Nippon Medical School)

  • Veronique Chobaz

    (University of Lausanne, CHUV)

  • Sonia Nasi

    (University of Lausanne, CHUV)

  • Mariela Castelblanco

    (University of Lausanne, CHUV)

  • Alexander So

    (University of Lausanne, CHUV)

  • Christine Lavanchy

    (University of Lausanne)

  • Hans Acha-Orbea

    (University of Lausanne)

  • Takeshi Nishino

    (Nippon Medical School)

  • Ken Okamoto

    (Nippon Medical School
    The University of Tokyo)

  • Nathalie Busso

    (University of Lausanne, CHUV)

Abstract

Xanthine oxidoreductase has been implicated in cancer. Nonetheless, the role played by its two convertible forms, xanthine dehydrogenase (XDH) and oxidase (XO) during tumorigenesis is not understood. Here we produce XDH-stable and XO-locked knock-in (ki) mice to address this question. After tumor transfer, XO ki mice show strongly increased tumor growth compared to wild type (WT) and XDH ki mice. Hematopoietic XO expression is responsible for this effect. After macrophage depletion, tumor growth is reduced. Adoptive transfer of XO-ki macrophages in WT mice increases tumor growth. In vitro, XO ki macrophages produce higher levels of reactive oxygen species (ROS) responsible for the increased Tregs observed in the tumors. Blocking ROS in vivo slows down tumor growth. Collectively, these results indicate that the balance of XO/XDH plays an important role in immune surveillance of tumor development. Strategies that inhibit the XO form specifically may be valuable in controlling cancer growth.

Suggested Citation

  • Teruo Kusano & Driss Ehirchiou & Tomohiro Matsumura & Veronique Chobaz & Sonia Nasi & Mariela Castelblanco & Alexander So & Christine Lavanchy & Hans Acha-Orbea & Takeshi Nishino & Ken Okamoto & Natha, 2019. "Targeted knock-in mice expressing the oxidase-fixed form of xanthine oxidoreductase favor tumor growth," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12565-z
    DOI: 10.1038/s41467-019-12565-z
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