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-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.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.
Highlights
In line with previous reports [19, 20], we found that in early mouse pancreatic intraepithelial neoplasia (mPanIN) lesions, the lesions presented as flat epithelial lesions composed of columnar cells with basally located nuclei and supranuclear mucin (Fig. 1b)
We found that Masson’s trichrome staining was detected in early precursor lesions such as acinar-to-ductal metaplasia (ADM) and mPanIN1 (Fig. 1f ), and it was exacerbated when the lesions progressed to late mPanIN and invasive Pancreatic ductal adenocarcinoma (PDAC) (Fig. 1g, h)
Metformin suppressed precursor lesion formation in KrasG12D/+; Pdx1-Cre (KC) mice To test whether the intake of metformin was sufficient to suppress pancreatic preneoplastic lesion formation, we investigated the cancer preventative effect of metformin in KC mouse model
Summary
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. 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. Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated mortality worldwide with a mortality that closely parallels incidence. Based on the pathological architecture and the degree of cytological atypia, precursor lesions are graded into several grades, including acinar-to-ductal
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
