Breast cancer–associated macrophages promote tumorigenesis by suppressing succinate dehydrogenase in tumor cells
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Tumor-associated macrophages (TAMs) can exist in pro- and anti-inflammatory states. Anti-inflammatory TAMs (also referred to as M2-polarized) generally suppress antitumor immune responses and enhance the metastatic progression of cancer. To explore the mechanisms behind this phenomenon, we isolated macrophages from mice and humans, polarized them ex vivo, and examined their functional interaction with breast cancer cells in culture and in mice. We found that anti-inflammatory TAMs promoted a metabolic state in breast cancer cells that supported various protumorigenic phenotypes. Anti-inflammatory TAMs secreted the cytokine TGF-β that, upon engagement of its receptors in breast cancer cells, suppressed the abundance of the transcription factor STAT1 and, consequently, decreased that of the metabolic enzyme succinate dehydrogenase (SDH) in the tumor cells. The decrease in SDH levels in tumor cells resulted in an accumulation of succinate, which enhanced the stability of the transcription factor HIF1α and reprogrammed cell metabolism to a glycolytic state. TAM depletion-repletion experiments in a 4T1 mouse model additionally revealed that anti-inflammatory macrophages promoted HIF-associated vascularization and expression of the immunosuppressive protein PD-L1 in tumors. The findings suggest that anti-inflammatory TAMs promote tumor-associated angiogenesis and immunosuppression by altering metabolism in breast cancer cells.
Date Issued
2020-10-06
Date Acceptance
2020-08-26
Citation
Science Signaling, 2020, 13 (652), pp.1-13
ISSN
1945-0877
Publisher
American Association for the Advancement of Science (AAAS)
Start Page
1
End Page
13
Journal / Book Title
Science Signaling
Volume
13
Issue
652
Copyright Statement
© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works https://www.sciencemag.org/about/science-licenses-journal-article-reuse
This is an article distributed under the terms of the Science Journals Default License https://www.sciencemag.org/about/science-licenses-journal-article-reuse.
This is an article distributed under the terms of the Science Journals Default License https://www.sciencemag.org/about/science-licenses-journal-article-reuse.
Identifier
https://stke.sciencemag.org/content/13/652/eaax4585
Subjects
0601 Biochemistry and Cell Biology
Publication Status
Published
Date Publish Online
2020-10-06