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2017 ; 16
(1
): 131
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Metformin suppresses cancer initiation and progression in genetic mouse models of
pancreatic cancer
#MMPMID28738823
Chen K
; Qian W
; Jiang Z
; Cheng L
; Li J
; Sun L
; Zhou C
; Gao L
; Lei M
; Yan B
; Cao J
; Duan W
; Ma Q
Mol Cancer
2017[Jul]; 16
(1
): 131
PMID28738823
show ga
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-Kras(G12D/+); Pdx1-Cre (KC) mouse model was established to
investigate the effect of metformin in pancreatic tumorigenesis suppression;
LSL-Kras(G12D/+); Trp53(fl/+); 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.
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