期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 216, 期 6, 页码 1345-1358出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20181616
关键词
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资金
- National Institutes of Health [R01DK102960, R01CA184494, R01DK107868, P30DK020595, F99CA212477]
- Cancer Research Foundation
- Avon Foundation
- Bernice Goldblatt Endowment Fellowship
- University of Chicago
- Department of Health via a National Institute for Health Research Biomedical Research Centre
Obesity is associated with increased incidence and severity of triple-negative breast cancer (TNBC); however, mechanisms underlying this relationship are incompletely understood. Here, we show that obesity reprograms mammary adipose tissue macrophages to a pro-inflammatory metabolically activated phenotype (MMe) that alters the niche to support tumor formation. Unlike pro-inflammatory M1 macrophages that antagonize tumorigenesis, MMe macrophages are pro-tumorigenic and represent the dominant macrophage phenotype in mammary adipose tissue of obese humans and mice. MMe macrophages release IL-6 in an NADPH oxidase 2 (NOX2)-dependent manner, which signals through glycoprotein 130 (GP130) on TNBC cells to promote stem-like properties including tumor formation. Deleting Nox2 in myeloid cells or depleting GP130 in TNBC cells attenuates obesity-augmented TNBC stemness. Moreover, weight loss reverses the effects of obesity on MMe macrophage inflammation and TNBC tumor formation. Our studies implicate MMe macrophage accumulation in mammary adipose tissue as a mechanism for promoting TNBC stemness and tumorigenesis during obesity.
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