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Molecular Cancer

, 16:131

First Online: 24 July 2017Received: 16 February 2017Accepted: 12 July 2017

Abstract

BackgroundPancreatic ductal adenocarcinoma PDAC is the fourth leading cause of cancer-associated mortality worldwide with an overall five-year survival rate less than 7%. Accumulating evidence has revealed the cancer preventive and therapeutic effects of metformin, one of the most widely prescribed medications for type 2 diabetes mellitus. However, its role in pancreatic cancer is not fully elucidated. Herein, we aimed to further study the preventive and therapeutic effects of metformin in genetically engineered mouse models of pancreatic cancer.

MethodsLSL-Kras; Pdx1-Cre KC mouse model was established to investigate the effect of metformin in pancreatic tumorigenesis suppression; LSL-Kras; Trp53; Pdx1-Cre KPC mouse model was used to evaluate the therapeutic efficiency of metformin in PDAC. Chronic pancreatitis was induced in KC mice by peritoneal injection of cerulein.

ResultsFollowing metformin treatment, pancreatic acinar-to-ductal metaplasia ADM and mouse pancreatic intraepithelial neoplasia mPanIN were decreased in KC mice. Chronic pancreatitis induced a stroma-rich and duct-like structure and increased the formation of ADM and mPanIN lesions, in line with an increased cytokeratin 19 CK19-stained area. Metformin treatment diminished chronic pancreatitis-mediated ADM and mPanIN formation. In addition, it alleviated the percent area of Masson’s trichrome staining, and decreased the number of Ki67-positive cells. In KPC mice, metformin inhibited tumor growth and the incidence of abdominal invasion. More importantly, it prolonged the overall survival.

ConclusionsMetformin inhibited pancreatic cancer initiation, suppressed chronic pancreatitis-induced tumorigenesis, and showed promising therapeutic effect in PDAC.

KeywordsMetformin Pancreatic cancer Tumorigenesis Chronic pancreatitis AbbreviationsADMAcinar-to-ductal metaplasia

CSCsCancer stem cells

ECMExtracellular matrix

EGFREpidermal growth factor receptor

EMTEpithelial to mesenchymal transition

KCKras; Pdx1-Cre

KPCKras; Trp53; Pdx1-Cre

MPanINMouse pancreatic intraepithelial neoplasia

PDACPancreatic ductal adenocarcinoma

PSCsPancreatic stellate cells

STAT3Signal transducer and activator of transcription 3

Electronic supplementary materialThe online version of this article doi:10.1186-s12943-017-0701-0 contains supplementary material, which is available to authorized users.

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Author: Ke Chen - Weikun Qian - Zhengdong Jiang - Liang Cheng - Jie Li - Liankang Sun - Cancan Zhou - Luping Gao - Meng Lei - Bin

Source: https://link.springer.com/







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