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

Abstract

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-1b 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-1b 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-a correlated with the onset of severe glandular atrophy. In comparison with Snustreated mice, TS-Elastase-IL-1b mice had an earlier onset and a greater extent of phenotypic changes, which were associated with up-regulation of TNF-a and increased expression of IL-6, TGF-b, 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.

Nimesulide inhibits proliferation and induces apoptosis of pancreatic cancer cells by enhancing expression of PTEN

“…The carcinogenic role of COX-2 overexpression has been demonstrated in a number of human malignancies, including pancreatic cancer (40). Overexpression of COX-2 is associated with tumor aggressiveness and growth in cancer biology (41,42).…”

Animal Models

“…In this scenario, a nongenic method of inducing pancreatitis is applied to GEMMs that do not exhibit a spontaneous disease phenotype. Investigators have successfully used this approach to implicate numerous signaling pathways in the development and severity of pancreatitis, including the complement system, [67][68][69][70][71] cytokine signaling, [72][73][74][75][76][77] immunoglobulins, 78,79 and, of course, protease (e.g. trypsin) pathways.…”

“…114 Similarly, exposure to tobacco induces flattening of ductal epithelial cells and significantly increases atrophy in the rEla1;sshIL-1β model of spontaneous pancreatitis. 76 Ethanol and smoking have also been introduced into genetic models of pancreatic cancer. Exposing KC (Pdx1-Cre; K-Ras +/LSLG12D ) mice to the Lieber-DeCarli alcohol diet in combination with cerulein results in synergistic and additive effects on PanIN formation.…”

Deploying Mouse Models of Pancreatic Cancer for Chemoprevention Studies

“…In rodents, cigarette smoke and its constituents cause chronic pancreatic inflammation and exocrine damage (43), serving as a precursor of pancreatitis and pancreatic cancer. The contribution of cigarette carcinogens to the development of pancreatic preneoplasms and cancer has been highlighted in vivo , including in EL-IL-1β mice (44) and in a 7,12-dimethylbenz[α]anthracene-induced mouse model, where nicotine provided robust progression of mPanIN to PDAC (45). Identifying the specific molecular and cellular effects of these carcinogens and their accompanying genetic lesions with respect to pancreatic cancer development has not been fully addressed in vivo .…”