Pancreatic duct glands are distinct ductal compartments that react to chronic injury and mediate Shh-induced metaplasia.

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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway.

We report a novel mouse model for the generation of sporadic tumors and show the efficiency of this approach by surveying Hedgehog (Hh)-related tumors. Up-regulation of the Hh pathway is achieved by conditionally regulated expression of an activated allele of Smoothened (R26-SmoM2) using either sporadic leakage or global postnatal induction of a ubiquitously expressed inducible Cre transgene (CAGGS-CreER). Following postnatal tamoxifen induction, CAGGS-CreER; R26-SmoM2 mice developed tumors with short latency and high penetrance. All mice exhibited rhabdomyosarcoma and basal cell carcinoma; 40% also developed medulloblastoma. In addition, mice showed a novel pancreatic lesion resembling low-grade mucinous cystic neoplasms in humans. In contrast, widespread activation of SmoM2 in the postnatal prostate epithelium results in no detectable morphologic outcome in 12-month-old mice. Comparison of gene expression profiles among diverse tumors identified several signature genes, including components of platelet-derived growth factor and insulin-like growth factor pathways, which may provide a common mechanistic link to the Hh-related malignancies. This experimental model provides a robust tool for exploring the process of Hh-dependent tumorigenesis and the treatment of such tumors. More generally, this approach provides a genetic platform for identifying tumorigenic potential in putative oncogenes and tumor suppressors and for more effective modeling of sporadic cancers in mice.