Simvastatin delay progression of pancreatic intraepithelial neoplasia and cancer formation in a genetically engineered mouse model of pancreatic cancer
| Autor: | Volker Fendrich, Matthias Lauth, Richard Knoop, Lars Plassmeier, Jens Waldmann, Detlef K. Bartsch, Moritz Sparn |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Genetically modified mouse
Simvastatin Pathology medicine.medical_specialty endocrine system diseases Endocrinology Diabetes and Metabolism Pancreatic Intraepithelial Neoplasia Mice Transgenic Mice Pancreatic cancer medicine Animals Pancreas Hepatology business.industry Gastroenterology Cancer medicine.disease Pancreatic Neoplasms Disease Models Animal Genes ras Genetically Engineered Mouse Disease Progression Cancer research Hydroxymethylglutaryl CoA Reductases CA19-9 business Carcinoma in Situ Immunostaining medicine.drug |
| Zdroj: | Pancreatology. 13:502-507 |
| ISSN: | 1424-3903 |
| Popis: | Background and aims 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 . Conclusion 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect