Pancreatic duct ligation reduces premalignant pancreatic lesions in a Kras model of pancreatic adenocarcinoma in mice

Marta Cáceres,Mónica Pérez,Luís Grande,Maria Villamonte,Rita Quesada,Mar Iglesias,Enrique Berjano,Patricia Sánchez-Velázquez,Dimitri Dorcaratto,Francisco X Real,Fernando Burdío,Ana Andaluz,Xavier Moll,Jaime Martinez De Villarreal

doi:10.1038/s41598-020-74947-4

Marta Cáceres, Mónica Pérez + Show 12 more

Open Access

PDF Available

https://doi.org/10.1038/s41598-020-74947-4

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

Pancreatic duct ligation (PDL) in the murine model has been described as an exocrine pancreatic atrophy-inducing procedure. However, its influence has scarcely been described on premalignant lesions. This study describes the histological changes of premalignant lesions and the gene expression in a well-defined model of pancreatic ductal adenocarcinoma by PDL. Selective ligation of the splenic lobe of the pancreas was performed in Ptf1a-Cre(+/ki); K-ras LSLG12Vgeo(+/ki) mice (PDL-Kras mice). Three experimental groups were evaluated: PDL group, controls and shams. The presence and number of premalignant lesions (PanIN 1–3 and Atypical Flat Lesions—AFL) in proximal (PP) and distal (DP) pancreas were studied for each group over time. Microarray analysis was performed to find differentially expressed genes (DEG) between PP and PD. Clinical human specimens after pancreaticoduodenectomy with ductal occlusion were also evaluated. PDL-Kras mice showed an intense pattern of atrophy in DP which was shrunk to a minimal portion of tissue. Mice in control and sham groups had a 7 and 10-time increase respectively of risk of high-grade PanIN 2 and 3 and AFL in their DP than PDL-Kras mice. Furthermore, PDL-Kras mice had significantly less PanIN 1 and 2 and AFL lesions in DP compared to PP. We identified 38 DEGs comparing PP and PD. Among them, several mapped to protein secretion and digestion while others such as Nupr1 have been previously associated with PanIN and PDAC. PDL in Ptf1a-Cre(+/ki); K-ras LSLG12Vgeo(+/ki) mice induces a decrease in the presence of premalignant lesions in the ligated DP. This could be a potential line of research of interest in some cancerous risk patients.

Highlights

Pancreatic duct ligation (PDL) in the murine model has been described as an exocrine pancreatic atrophy-inducing procedure
In the Kras mice, we identified a majority of PanIN 1 lesions (n = 6290; 97%), followed in number by atypical flat lesions (AFL) (n = 160; 2.5%), PanIN 2 and PanIN 3 high-grade lesions (n = 32; 0.4% and n = 10; 0.1%, respectively) and frequent areas of focal lobulicentric atrophy as already described in these models[26]
Mutated or useless cells are better dead and cell suicide through apoptosis may achieve this goal and this could be relevant in many diseases

Summary

Introduction

Pancreatic duct ligation (PDL) in the murine model has been described as an exocrine pancreatic atrophy-inducing procedure. This study describes the histological changes of premalignant lesions and the gene expression in a well-defined model of pancreatic ductal adenocarcinoma by PDL. Ultrastructural and immunohistochemical studies in normal and transgenic mice have demonstrated that after experimental pancreatic duct ligation (PDL), most of the acinar cells are rapidly and massively deleted by apoptosis-mediated exocrine atrophy. This process is regulated by p53 active p rotein[13,16,17,18,19]. Our group has demonstrated a complete acinar cell deletion both in short and long-term evolution with no sign of acinar regeneration after an efficient model of PDL in murine and in pig normal pancreas[20,21]

Methods

Results

Conclusion