The Presence of Interleukin-13 at Pancreatic ADM/PanIN Lesions Alters Macrophage Populations and Mediates Pancreatic Tumorigenesis

Cell Reports

卷:19

Nabeel Bardeesy¹  Geou-Yarh Liou²  Peter Storz²  Brandy H. Edenfield²  Ligia Bastea²  Alicia Fleming²  Heike Döppler²  Lizhi Zhang³  David W. Dawson⁴ 

[1] Center for Cancer Research, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, 02115 MA, USA;

[2] Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA;

[3] Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN 55905, USA;

[4] Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;

关键词: pancreatic cancer;    PanIN;    metaplasia;    Tuft cells;    macrophages;    polarization;    IL-13;    interleukin-13;    CCL-2;    IL-1ra;   

DOI  :  10.1016/j.celrep.2017.04.052

来源: DOAJ

【 摘 要 】

The contributions of the innate immune system to the development of pancreatic cancer are still ill defined. Inflammatory macrophages can initiate metaplasia of pancreatic acinar cells to a duct-like phenotype (acinar-to-ductal metaplasia [ADM]), which then gives rise to pancreatic intraepithelial neoplasia (PanIN) when oncogenic KRas is present. However, it remains unclear when and how this inflammatory macrophage population is replaced by tumor-promoting macrophages. Here, we demonstrate the presence of interleukin-13 (IL-13), which can convert inflammatory into Ym1+ alternatively activated macrophages, at ADM/PanIN lesions. We further show that Ym1+ macrophages release factors, such as IL-1ra and CCL2, to drive pancreatic fibrogenesis and tumorigenesis. Treatment of mice expressing oncogenic KRas under an acinar cell-specific promoter with a neutralizing antibody for IL-13 significantly decreased the accumulation of alternatively activated macrophages at these lesions, resulting in decreased fibrosis and lesion growth.

【 授权许可】

Unknown