Journal
CANCER CELL
Volume 25, Issue 5, Pages 621-637Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2014.03.014
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Funding
- National Institute of General Medical Sciences (NIGMS) [T32GMO66691]
- Pancreatic Cancer Action Network-AACR Fellowship [12-40-25-MCAL]
- Conquer Cancer Foundation
- National Cancer Institute (NCI) [P01 CA134292]
- Paul K. Neumann Professorship in Pancreatic Cancer at Johns Hopkins University
- PanCAN-AACR Pathway to Leadership Award
- NCI [F32 CA157044, T32CA126607]
- ImmixGroup Foundation Fellowship
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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.
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