Ductal obstruction promotes formation of preneoplastic lesions from the pancreatic ductal compartment.
Int J Cancer
; 144(10): 2529-2538, 2019 05 15.
Article
in En
| MEDLINE
| ID: mdl-30412288
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Pancreatic Ducts
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Pancreatic Neoplasms
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Pancreatitis
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Precancerous Conditions
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Carcinoma, Pancreatic Ductal
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Carcinogenesis
Type of study:
Risk_factors_studies
Limits:
Animals
Language:
En
Year:
2019
Type:
Article