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

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.

• Authors: Ke Chen, Weikun Qian, Zhengdong Jiang, Liang Cheng, Jie Li, Liankang Sun, Cancan Zhou, Luping Gao, Meng Lei, Bin Yan, Junyu Cao, Wanxing Duan, Qingyong Ma
• Journal: Molecular cancer (Mol Cancer) Vol. 16 Issue 1 Pg. 131 (07 24 2017) ISSN: 1476-4598 [Electronic] England
• PMID: 28738823 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Keratin-19
• Ki-67 Antigen
• Metformin

Topics

• Animals
• Carcinogenesis (drug effects, metabolism)
• Carcinoma in Situ (drug therapy, metabolism)
• Carcinoma, Pancreatic Ductal (drug therapy, metabolism)
• Disease Models, Animal
• Disease Progression
• Keratin-19 (metabolism)
• Ki-67 Antigen (metabolism)
• Metformin (pharmacology)
• Mice
• Mice, Transgenic
• Pancreas (drug effects)
• Pancreatic Ducts (drug effects, metabolism)
• Pancreatic Neoplasms (drug therapy, metabolism)
• Pancreatitis, Chronic (drug therapy, metabolism)