Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer

DOI PDF 被引用文献1件
  • Payal Tiwari
    Committee on Cancer Biology, The University of Chicago, Chicago, IL 1
  • Ariane Blank
    Committee on Cancer Biology, The University of Chicago, Chicago, IL 1
  • Chang Cui
    Committee on Cancer Biology, The University of Chicago, Chicago, IL 1
  • Kelly Q. Schoenfelt
    Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 2
  • Guolin Zhou
    Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 2
  • Yanfei Xu
    Department of Surgery and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine of Northwestern University, Northwestern University, Chicago, IL 3
  • Galina Khramtsova
    Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL 4
  • Funmi Olopade
    Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL 4
  • Ajay M. Shah
    School of Cardiovascular Medicine and Sciences, King’s College, London British Hearth Foundation Centre, London, UK 6
  • Seema A. Khan
    Department of Surgery and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine of Northwestern University, Northwestern University, Chicago, IL 3
  • Marsha Rich Rosner
    Committee on Cancer Biology, The University of Chicago, Chicago, IL 1
  • Lev Becker
    Committee on Cancer Biology, The University of Chicago, Chicago, IL 1

説明

<jats:p>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.</jats:p>

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