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Cancer Cell. 2014 May 12;25(5):621-37. doi: 10.1016/j.ccr.2014.03.014.

Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia.

Author information

1
Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA; Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
2
Department of Surgery and McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
3
Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA.
4
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21205, USA.
5
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
6
Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21205, USA.
7
Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
8
Department of Surgery and McKusick Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: leachs@mskcc.org.

Abstract

Many human cancers are dramatically accelerated by chronic inflammation. However, the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of pancreatic intraepithelial neoplasia (PanIN), we found that Kras(G12D) induces expression of functional IL-17 receptors on PanIN epithelial cells and also stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by associated chronic pancreatitis, resulting in functional in vivo changes in PanIN epithelial gene expression. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation.

PMID:
24823639
PMCID:
PMC4072043
DOI:
10.1016/j.ccr.2014.03.014
[Indexed for MEDLINE]
Free PMC Article

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