Potential carcinogenic effects of cigarette smoke and Swedish moist snuff on pancreas: a study using a transgenic mouse model of chronic pancreatitis.

The risk of pancreatic cancer is increased in both Snus (the Swedish variant of oral smokeless tobacco) users and, to a greater extent, in cigarette smokers. Concurrent chronic pancreatitis further increases the risk in cigarette smokers. Little is known about the mechanism by which cigarette smoke or Snus increase the risk of pancreatic cancer in individuals with chronic pancreatitis. This study examined the carcinogenic effects of an aqueous extract of cigarette smoke (tobacco smoke, TS) or Snus in an Elastase-IL-1beta transgenic mouse model of chronic pancreatitis. Both transgenic and wild-type (WT) mice were fed diluted TS water or Snus-containing diet for up to 15 months, and monitored for phenotypic and molecular changes in the pancreas. Both TS- and Snus-treated Elastase-IL-1beta mice, but not WT mice, developed significant pancreatic ductal epithelial flattening and severe glandular atrophy compared with untreated transgenic mice. Ductal epithelial cells displayed a high proliferative index, minimal apoptosis, and induction of COX-2 in the setting of chronic inflammation. Up-regulation of TNF-alpha correlated with the onset of severe glandular atrophy. In comparison with Snus-treated mice, TS-Elastase-IL-1beta mice had an earlier onset and a greater extent of phenotypic changes, which were associated with up-regulation of TNF-alpha and increased expression of IL-6, TGF-beta, and SDF-1. Collectively, these findings provide new insights into the mechanism by which tobacco products are likely to promote carcinogenesis in the setting of chronic pancreatitis.