Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer

Molecular Cancer

Meng Lei¹  Weikun Qian¹  Liang Cheng¹  Qingyong Ma¹  Zhengdong Jiang¹  Jie Li¹  Bin Yan¹  Liankang Sun¹  Junyu Cao¹  Wanxing Duan¹  Luping Gao¹  Cancan Zhou¹  Ke Chen¹ 

[1] Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an Jiaotong University;

关键词: Metformin;    Pancreatic cancer;    Tumorigenesis;    Chronic pancreatitis;   

DOI  :  10.1186/s12943-017-0701-0

来源: DOAJ

【 摘 要 】

Abstract Background Pancreatic 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. Methods LSL-KrasG12D/+; Pdx1-Cre (KC) mouse model was established to investigate the effect of metformin in pancreatic tumorigenesis suppression; LSL-KrasG12D/+; Trp53fl/+; 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. Results Following 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. Conclusions Metformin inhibited pancreatic cancer initiation, suppressed chronic pancreatitis-induced tumorigenesis, and showed promising therapeutic effect in PDAC.

【 授权许可】

Unknown