Abstract 5188: Chronic pancreatitis induces the cancer-related gene expressions .
Authors: Sakata Kazuya , Ohmuraya Masaki , Hashimoto Daisuke , Nitta Hidetoshi , Imai Katunori , Hayashi Hiromitu , Ikuta Yoshiaki , Chikamoto Akira , Beppu Tooru , Baba Hideo 
Published: August 2014

Background & Aims: Several studies reported that chronic pancreatitis (CP) is a risk factor for pancreatic ductal adenocarcinoma (PDAC). The loss-of-function mutations of serine protease inhibitor Kazal type 1 (SPINK1) gene are associated with various forms of hereditary pancreatitis.We previously showed that deletion of Spink3,the mouse homologue of human SPINK1, causes pancreatitis-like changes in the mouse. A careful molecular and pathological analysis of evolving PDAC has revealed a characteristic pattern of genetic lesions. The field is now faced with the challenge of understanding how these signature genetic lesions _ mutations of cancer-related genes _ contribute to the biological characteristics and evolution of this disease. The aim of this study was to rescue the Spink3−/- phenotype by generating Spink3−/- mice with knocked-in SPINK1, and to characterize time-dependent changes of cancer-related genes in the pancreas in this genetic model. Methods: We placed CAG promoter-SPINK1 minigene(SP1) into diaphanous homolog 2 (Diap2) locus, which is located on X chromosome, using the Cre-Lox technology. X-inactivation is a process whereby one of the two copies of the X chromosome present in female mammals is inactivated. By utilizing X-inactivation,we were able to create mice in which SPINK level was partially, but not completely, reduced compared with the wild type. The SP1 knock-in mice(male YXSP1 and female XSP1/SP1 or XSP1/+) were crossed to Spink3+/- mice, thus generating Spink3−/−SP1 knock-in mice. Mice were followed up for up to 6 months.Time-dependent changes in pancreatic histology, stellate cell activation, and serum amylase were measured. Results: Spink3−/−YXSP1,as well as Spink3−/−XSP1/SP1 mice in which SP1 transgene was present on both X chromosomes, showed no abnormalities in pancreas or any other organ during the 6 months of observation, indicating that human Spink1 rescues Spink3 deficiency in mice. Spink3−/−XSP1/+ mice in which SP1 transgene is present on only one of the two X chromosomes, showed slight growth retardation but were healthy and fertile. Pancreas of Spink3−/−XSP1/+ mice at birth contained both normal and degenerated acinar cells, with accumulation of autophagic vacuoles. The Spink3−/−XSP1/+ mice time-dependently developed pathologic features of chronic tissue damage, including loss of acinar cells, intralobular fibrosis with activated stellate cells. Interlobular ducts were dilated and contained protein plugs, which resembled chronic pancreatitis in human. Older mice displayed acinar-ductal metaplasia and prominent expression of proto-oncogenes Egfr, Her2, and Ras. Conclusions: CP may contribute to carcinogenesis by preventing the senescence barrier characteristic of normal pancreas. Antiinflammatory treatment of CP patients may reduce their risk of developing PDAC.

Citation Format: Kazuya Sakata, Masaki Ohmuraya, Daisuke Hashimoto, Hidetoshi Nitta, Katunori Imai, Hiromitu Hayashi, Yoshiaki Ikuta, Akira Chikamoto, Tooru Beppu, Hideo Baba. Chronic pancreatitis induces the cancer-related gene expressions . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5188. doi:10.1158/1538-7445.AM2013-5188