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In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia.

ABSTRACT: Chronic injury results in regeneration of normal pancreatic tissue and formation of a metaplasia of ductal phenotype. Metaplastic ductal lesions are seen in pancreatitis as well as in specimens of pancreatic cancer and are thought to represent a condition with increased risk of neoplasia. Acinar-to-ductal transdifferentiation is thought to be the source of this metaplasia. This has been suggested for flat duct-like lesions called tubular complexes and for lesions exhibiting a mucinous metaplasia. However, available studies are based on interpretation of static data rather than on direct evidence. Transdifferentiation from acinar to ductal cells has never been confirmed in the adult pancreas.Here, we use Cre-loxP-based genetic lineage tracing in vivo to investigate whether transdifferentiation of acinar cells contributes to regeneration and metaplasia in pancreatitis.The results show that transdifferentiation does not play a role in regeneration of normal tissue. Acinar cells are regenerated by preexisting acinar cells and not from other cell types. Three different types of metaplastic ductal lesions are observed and analyzed. Whereas the majority of metaplastic lesions are not of acinar origin, acinar-to-ductal transdifferentiation is identified in a minority of mucinous metaplastic lesions.Here, we provide direct evidence that acinar-to-ductal transdifferentiation occurs in the adult pancreas in vivo. However, it accounts for only a minority of metaplastic lesions.

SUBMITTER: Strobel O

PROVIDER: S-EPMC2254582 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia.

Strobel Oliver O Dor Yuval Y Alsina Janivette J Stirman Amy A Lauwers Gregory G Trainor Amanda A Castillo Carlos Fernández-Del CF Warshaw Andrew L AL Thayer Sarah P SP

Gastroenterology 20070914 6

<h4>Background & aims</h4>Chronic injury results in regeneration of normal pancreatic tissue and formation of a metaplasia of ductal phenotype. Metaplastic ductal lesions are seen in pancreatitis as well as in specimens of pancreatic cancer and are thought to represent a condition with increased risk of neoplasia. Acinar-to-ductal transdifferentiation is thought to be the source of this metaplasia. This has been suggested for flat duct-like lesions called tubular complexes and for lesions exhibi ...[more]

PMID: 18054571

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Project description:Background and aimsAnimal data show that the presence of an oncogenic Kras mutation in pancreatic acinar cells leads to acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN), and pancreatic ductal adenocarcinoma (PDAC). Inflammatory macrophages play an important role in the formation of ADMs and transition to PanINs. Epidemiologically, statins are associated with a reduced risk of PDAC. We investigated whether statins inhibit inflammatory cytokine production in macrophages and whether this leads to reduced ADM formation.MethodsThe efficacy of statins on inflammatory cytokine production in 2 macrophage cell lines was measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of macrophage-conditioned medium on ADM in primary pancreatic acinar cells was investigated. Mouse pancreatic tissue samples were analyzed for macrophage numbers, cytokine levels, and neoplastic/dysplastic area.ResultsLipophilic statins prevented inflammatory cytokine production in Raw264.7 and J774A.1 cells stimulated by lipopolysaccharide. The inhibitory effect of statins was mediated by inhibition of mevalonate and geranylgeranyl pyrophosphate synthesis and disruption of the actin cytoskeleton but not by a reduction in intracellular cholesterol. Treatment of macrophages with lipophilic statins also blocked ADM formation of primary pancreatic acinar cells. Furthermore, oral administration of simvastatin was associated with a reduction in the number of intrapancreatic macrophages, decreased inflammatory cytokine levels in the pancreas, and attenuated ADM/PanIN formation in mice.ConclusionOur data support the hypothesis that statins oppose early PDAC development by their effects on macrophages and ADM formation. The inhibitory actions of statins on macrophages may collaborate with direct inhibitory effects on transformed pancreatic epithelial cells, which cumulatively may reduce early PDAC development and progression.

Dataset Information

In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia.

Publications

In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia.

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