Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia.
Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia.
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DOI：
10.1016/j.ccr.2014.03.014
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发表时间：
2014-05-12
期刊：
影响因子：
50.3
通讯作者：
Leach SD
中科院分区：
文献类型：
--
作者：
McAllister F;Bailey JM;Alsina J;Nirschl CJ;Sharma R;Fan H;Rattigan Y;Roeser JC;Lankapalli RH;Zhang H;Jaffee EM;Drake CG;Housseau F;Maitra A;Kolls JK;Sears CL;Pardoll DM;Leach SD
许多人类癌症会因慢性炎症而显著加速。然而，介导这种效应的特定细胞和分子元件在很大程度上仍然未知。使用胰腺上皮内瘤变（PanIN）的小鼠模型，我们发现KrasG 12 D诱导PanIN上皮细胞上功能性IL-17受体的表达，并且还刺激产生IL-17的免疫细胞浸润胰腺基质。这两种效应都被相关的慢性胰腺炎增强，导致PanIN上皮基因表达的功能性体内变化。强制性IL-17过表达显著加速PanIN的起始和进展，而使用遗传或药理学技术抑制IL-17信号传导有效地防止PanIN形成。总之，这些研究表明，造血-上皮IL-17信号传导轴是PanIN形成的有效和必要的驱动因素。
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 KrasG12D 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.