Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression.
ATP-Binding Cassette Transporters
/ genetics
Animals
Biological Transport
/ physiology
Bone Marrow Cells
/ pathology
Cell Membrane
/ metabolism
Cells, Cultured
Cellular Reprogramming
/ physiology
Cholesterol
/ metabolism
Disease Progression
Female
Macrophages
/ physiology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neoplasms
/ immunology
Tumor Escape
/ physiology
Tumor Microenvironment
/ physiology
IL-4 signaling
cholesterol efflux
lipid rafts
ovarian cancer
tumor-associated macrophages
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
04 06 2019
04 06 2019
Historique:
received:
06
11
2018
revised:
01
01
2019
accepted:
26
02
2019
pubmed:
2
4
2019
medline:
15
8
2020
entrez:
2
4
2019
Statut:
ppublish
Résumé
Macrophages possess intrinsic tumoricidal activity, yet tumor-associated macrophages (TAMs) rapidly adopt an alternative phenotype within the tumor microenvironment that is marked by tumor-promoting immunosuppressive and trophic functions. The mechanisms that promote such TAM polarization remain poorly understood, but once identified, they may represent important therapeutic targets to block the tumor-promoting functions of TAMs and restore their anti-tumor potential. Here, we have characterized TAMs in a mouse model of metastatic ovarian cancer. We show that ovarian cancer cells promote membrane-cholesterol efflux and depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4-mediated reprogramming, including inhibition of IFNγ-induced gene expression. Genetic deletion of ABC transporters, which mediate cholesterol efflux, reverts the tumor-promoting functions of TAMs and reduces tumor progression. These studies reveal an unexpected role for membrane-cholesterol efflux in driving TAM-mediated tumor progression while pointing to a potentially novel anti-tumor therapeutic strategy.
Identifiants
pubmed: 30930171
pii: S1550-4131(19)30128-7
doi: 10.1016/j.cmet.2019.02.016
pii:
doi:
Substances chimiques
ATP-Binding Cassette Transporters
0
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1376-1389.e4Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/I01246X/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.