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

Nature Communications
Teruo KusanoNathalie Busso

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.

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Citations

Jan 21, 2021·Free Radical Biology & Medicine·Yoshiro TanakaMichihiro Yoshimura
Feb 16, 2021·Redox Biology·Kilian B Kennel, Florian R Greten
Feb 27, 2021·Frontiers in Cell and Developmental Biology·Sonia NasiNathalie Busso
Apr 4, 2021·International Journal of Molecular Sciences·Shuichi ShibuyaTakahiko Shimizu
Apr 9, 2021·Science Advances·Yaoyao XiaWenkai Ren
Jun 30, 2021·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Claudia Garrido, Silke Leimkühler

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Methods Mentioned

BETA
xenograft
X-ray
electrophoresis
FACS
ELISA
flow cytometry
PMA
FCS
fluorescence-activated cell sorting
PCR

Software Mentioned

qBasePlus
FlowJoX ( Tree Star )

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