Simvastatin delay progression of pancreatic intraepithelial neoplasia and cancer formation in a genetically engineered mouse model of pancreatic cancer.
OBJECTIVE
Pancreatic cancer is among the most dismal of human malignancies. There are no chemopreventive strategies for pancreatic cancer or its precursor lesions, pancreatic intraepithelial neoplasia (PanINs). Recent evidence suggests that statins have potential chemopreventive abilities. In this study, we used a genetically engineered mouse model of pancreatic cancer to evaluate the chemopreventive potential of this drug.


METHODS
Simvastatin was injected i.p. in LsL-Kras(G12D); Pdx1-Cre or LsL-Kras(G12D);LsL-Trp53(R172H);Pdx1-Cre mice. After five months, animals were sacrificed. The effect of simvastatin was evaluated by histopathological analyses, immunostaining, and real-time PCR.


RESULTS
After five months of treatment, simvastatin was able to significantly delay progression of mPanINs in LsL-Kras(G12D); Pdx1-Cre mice. Furthermore, formation of invasive pancreatic cancer in LsL-Kras(G12D); LsL-Trp53(R172H); Pdx1-Cre transgenic mice was partially inhibited by simvastatin. Invasive murine pancreatic cancer was identified in 9 of 12 (75%) LsL-Kras(G12D); LsL-Trp53(R172H);Pdx1-Cre untreated control mice. In contrast, transgenic mice treated with Simvastatin, only 4 out of 10 (40%, p = 0.004) developed murine pancreatic cancer during the study. Using real-time PCR we found a significant up-regulation of Hmgcr as sign of blocking HMG-CoA reductase, a key enzyme in the cholesterol biosynthesis. This shows our ability to achieve effective pharmacologic levels of simvastatin during pancreatic cancer formation in vivo.


CONCLUSIONS
Using a transgenic mouse model that recapitulates human pancreatic cancer, this study provides first evidence that simvastatin is an effective chemopreventive agent by delaying the progression of PanINs and partially inhibit the formation of murine pancreatic cancer.
Department of Surgery, Philipps-University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. Electronic address: fendrich@med.uni-marburg.de.
Volker
V
Fendrich
Moritz
M
Sparn
Matthias
M
Lauth
Richard
R
Knoop
Lars
L
Plassmeier
Detlef K
DK
Bartsch
Jens
J
Waldmann
D000818:Animals; D002278:Carcinoma in Situ / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D011905:Genes, ras; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000201:enzymology / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000517:prevention & control*; D019821:Simvastatin / Q000627:therapeutic use*
D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases
Chemoprevention; PanINs; Pancreatic cancer; Simvastatin; Statins