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Cell Rep. 2017 May 16;19(7):1322-1333. doi: 10.1016/j.celrep.2017.04.052.

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

Author information

1
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
2
Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
3
Department of Laboratory Medicine & Pathology, Mayo Clinic, Rochester, MN 55905, USA.
4
Center for Cancer Research, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, 02115 MA, USA.
5
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: storz.peter@mayo.edu.

Abstract

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.

KEYWORDS:

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

PMID:
28514653
PMCID:
PMC5510483
DOI:
10.1016/j.celrep.2017.04.052
[Indexed for MEDLINE]
Free PMC Article

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