Ductal obstruction promotes formation of preneoplastic lesions from the pancreatic ductal compartment.

Abstract

Pancreatitis is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC). Previous studies in mice have demonstrated that pancreatitis contributes to oncogenic Kras-driven carcinogenesis, probably initiated in acinar cells; however, oncogenic Kras alone or in combination with caerulein-induced pancreatitis is not sufficient in initiating PDAC from the ductal compartment. We thus introduced ductal obstruction - which induces a more severe form of pancreatitis - by pancreatic ductal ligation in mice harbouring oncogenic Kras. This induced a particular phenotype with highly proliferative nonmucinous cells with nuclear atypia. Around these lesions, there was a significant proliferation of activated fibroblasts and infiltration of immune cells, corroborating the pathological features of preneoplastic lesions. Lineage-tracing experiments revealed that these preneoplastic cells derived from two distinctive cellular sources: acinar and ductal cells. Phenotypic characterisation revealed that the duct-derived preneoplastic lesions show a high proliferative potential with persistent activation of tumour-promoting inflammatory pathways while the acinar-derived ones were less proliferative with persistent p53 activation. Furthermore, the duct-derived preneoplastic cells have a particularly high nuclear-to-cytoplasmic ratio. These data demonstrate that ductal obstruction promotes preneoplastic lesion formation from the pancreatic ductal compartment.

• Authors: Tao Cheng, Zhiheng Zhang, Ziying Jian, Susanne Raulefs, Anna Melissa Schlitter, Katja Steiger, Nadja Maeritz, Yamin Zhao, Shanshan Shen, Xiaoping Zou, Güralp O Ceyhan, Helmut Friess, Jörg Kleeff, Christoph W Michalski, Bo Kong
• Journal: International journal of cancer (Int J Cancer) Vol. 144 Issue 10 Pg. 2529-2538 (05 15 2019) ISSN: 1097-0215 [Electronic] United States
• PMID: 30412288 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 UICC.

Chemical References

• Tumor Suppressor Protein p53

Topics

• Acinar Cells (pathology)
• Animals
• Carcinogenesis (genetics, pathology)
• Carcinoma, Pancreatic Ductal (genetics, pathology)
• Cell Proliferation (genetics)
• Cell Transformation, Neoplastic (genetics, pathology)
• Fibroblasts (pathology)
• Mice
• Mice, Inbred C57BL
• Pancreatic Ducts (pathology)
• Pancreatic Neoplasms (genetics, pathology)
• Pancreatitis (genetics, pathology)
• Precancerous Conditions (genetics, pathology)
• Tumor Suppressor Protein p53 (genetics)
• Pancreatic Neoplasms