Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Gastroenterology. 2010 Mar;138(3):1166-77. doi: 10.1053/j.gastro.2009.12.005. Epub 2009 Dec 21.
BACKGROUND & AIMS: Pancreatic intraepithelial neoplasia (PanIN) are pancreatic cancer precursor lesions of unclear origin and significance. PanIN aberrantly express sonic hedgehog (Shh), an initiator of pancreatic cancer, and gastrointestinal mucins. A majority of PanIN are thought to arise from ducts. We identified a novel ductal compartment that is gathered in gland-like outpouches (pancreatic duct glands [PDG]) of major ducts and characterized its role in injury and metaplasia.
The ductal system was analyzed in normal pancreata and chronic pancreatitis in humans and mice. Anatomy was assessed by serial hematoxylin and eosin sections and scanning electron microscopy of corrosion casts. Expression of mucins and developmental genes and proliferation were assessed by immunohistochemistry or real-time quantitative polymerase chain reaction. Effects of Shh on ductal cells were investigated by exposure to Shh in vitro and transgenic misexpression in vivo.
Three-dimensional analysis revealed blind-ending outpouches of ducts in murine and human pancreata. These PDG are morphologically and molecularly distinct from normal ducts; even in normal pancreata they display PanIN and metaplastic features, such as expression of Shh and gastric mucins. They express other developmental genes, such as Pdx-1 and Hes-1. In injury, Shh is up-regulated along with gastric mucins. Expansion of the PDG compartment results in a mucinous metaplasia. Shh promotes this transformation in vitro and in vivo.
PDG are distinct gland-like mucinous compartments with a distinct molecular signature. In response to injury, PDG undergo an Shh-mediated mucinous gastrointestinal metaplasia with PanIN-like features. PDG may provide a link between Shh, mucinous metaplasia, and neoplasia.
胰腺上皮内瘤变（PanIN）是胰腺癌的前体病变，其起源和意义尚不清楚。PanIN 异常表达 sonic hedgehog（Shh），这是胰腺癌的启动子，以及胃肠道粘蛋白。大多数 PanIN 被认为起源于导管。我们发现了一种新的导管隔室，它聚集在主要导管的腺体样外凸（胰腺导管腺 [PDG]）中，并描述了其在损伤和化生中的作用。
在人类和小鼠的正常胰腺和慢性胰腺炎中分析导管系统。通过连续苏木精和伊红切片以及腐蚀铸型的扫描电子显微镜评估解剖结构。通过免疫组织化学或实时定量聚合酶链反应评估粘蛋白和发育基因的表达以及增殖情况。通过体外暴露于 Shh 和体内过表达转基因来研究 Shh 对导管细胞的影响。
三维分析显示，鼠和人胰腺中的导管有盲端外凸。这些 PDG 在形态和分子上与正常导管不同；即使在正常胰腺中，它们也显示出 PanIN 和化生特征，如 Shh 和胃粘蛋白的表达。它们还表达其他发育基因，如 Pdx-1 和 Hes-1。在损伤中，Shh 与胃粘蛋白一起上调。PDG 隔室的扩张导致粘蛋白化生。Shh 在体外和体内促进这种转化。
PDG 是具有独特分子特征的独特的腺体样粘蛋白隔室。在受到损伤时，PDG 经历了一种由 Shh 介导的粘蛋白胃肠道化生，具有 PanIN 样特征。PDG 可能为 Shh、粘蛋白化生和肿瘤之间提供了联系。
