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

Authors :
Kusano T
Ehirchiou D
Matsumura T
Chobaz V
Nasi S
Castelblanco M
So A
Lavanchy C
Acha-Orbea H
Nishino T
Okamoto K
Busso N
Source :
Nature communications [Nat Commun] 2019 Oct 28; Vol. 10 (1), pp. 4904. Date of Electronic Publication: 2019 Oct 28.
Publication Year :
2019

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.

Details

Language :
English
ISSN :
2041-1723
Volume :
10
Issue :
1
Database :
MEDLINE
Journal :
Nature communications
Publication Type :
Academic Journal
Accession number :
31659168
Full Text :
https://doi.org/10.1038/s41467-019-12565-z