流出
重编程
肿瘤进展
癌症研究
生物
肿瘤微环境
巨噬细胞极化
细胞生物学
胆固醇
卵巢癌
表型
癌症
细胞
肿瘤细胞
基因
内分泌学
生物化学
遗传学
作者
Pieter Goossens,Juan Rodríguez-Vita,Anders Etzerodt,Marion Massé,Olivia Rastoin,Victoire Gouirand,Thomas Ulas,Olympia Papantonopoulou,Miranda Van Eck,Nathalie Auphan-Anezin,Magali Bébien,Christophe Verthuy,Thien‐Phong Vu Manh,Martin Turner,Marc Dalod,Joachim L. Schultze,Toby Lawrence
出处
期刊:Cell Metabolism
[Elsevier]
日期:2019-06-01
卷期号:29 (6): 1376-1389.e4
被引量:252
标识
DOI:10.1016/j.cmet.2019.02.016
摘要
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.
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