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

作者：Cheng, Tao; Zhang, Zhiheng; Jian, Ziying; Raulefs, Susanne; Schlitter, Anna Melissa; Steiger, Katja; Maeritz, Nadja; Zhao, Yamin; Shen, Shanshan; Zou, Xiaoping; Ceyhan, Gueralp O.; Friess, Helmut; Kleeff, Joerg; Michalski, Christoph W.; Kong, Bo^*

来源：International Journal of Cancer, 2019, 144(10): 2529-2538.

DOI：10.1002/ijc.31981

• pancreatic cancer
• pancreatitis
• ductal obstruction
• ADM
• TC

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.

• 出版日期2019-5-15
• 单位南京大学