Chronic pancreatitis and pancreatic cancer: prediction and mechanism.
We investigated the SPINK 1 mutations in 156 sporadic pancreatic cancer (PCa), and 8 pancreatic cancer with chronic pancreatitis (CPPCa) patients, and in 527 healthy subjects. The results demonstrated that 3 of 8 patients with CPPCa (37.5%) had the SPINK 1 gene N34S mutation. In addition, 3 of 156 sporadic PCa patients (1.9%) and 1 of them (0.6%) had the N34S and IVS3+2T>C mutation, respectively. The combined frequency of 2.5% was significantly higher than that of healthy subjects (0.38%), suggesting that the SPINK 1 mutation is an important risk factor for the development of pancreatic cancer. To investigate the genetic difference between sporadic PCa and CPPCa, we investigated several factors involved in the pathogenesis of PCa in 6 CPPCa and 15 sporadic PCa patients. The factors examined were genes including K-ras, p53, smad 4, p-smad 1, CXCL 14, NF-kB subunit p65 and Wnt 5a. No significant difference was found in the comparative examination of these factors, suggesting that the molecular disorders appeared to occur similarly in CPPCa as well as sporadic PCa. To assess the role of fibrosis in pancreatic carcinogenesis, we investigated the effects of pancreatic stellate cells (PSCs), which are largely responsible for pancreatic fibrogenesis, on duct cells, in vitro and in vivo. Activated PSCs were found surrounding precancerous duct cells in the tissues of a dimethylbenzanthracene mouse model and those of human PCa. Consistently, human pancreatic epithelial duct cells cultured with PSC conditioned media showed increased cell proliferation and colony formation, suggesting that PSCs may promote pancreatic ductal tumorigenesis.
Shimosegawa
Tooru
T
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai city, Miyagi, Japan. tshimosegawa@int3.med.tohoku.ac.jp
Kume
Kiyoshi
K
Satoh
Kennichi
K
D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D004847:Epithelial Cells; D005260:Female; D005787:Gene Frequency; D006801:Humans; D051379:Mice; D008875:Middle Aged; D020125:Mutation, Missense; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D017354:Point Mutation; D011110:Polymorphism, Genetic; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014992:Xylenes / Q000633:toxicity
D002352:Carrier Proteins; C486642:SPINK1 protein, human; D014992:Xylenes; D014359:Trypsin Inhibitor, Kazal Pancreatic