Progression to Intraepithelial Neoplasia

nloaded onic infectious diseases, such as Helicobacter pylori infection, can promote cancer in a large part through ion of chronic inflammation. Oncogenic K-ras mutation in epithelial cells activates inflammatory pathwhich could compensate for a lack of infectious stimulus. Gastric histopathology and putative progenitor rs [doublecortin and calcium/calmodulin-dependent protein kinase-like 1 (Dcamkl1) and keratin 19 (K19)] -K-ras-V12 (K19-kras) transgenic mice were assessed at 3, 6, 12, and 18 months of age, in comparison with bacter felis–infected wild-type littermates. Inflammation was evaluated by reverse transcription–PCR of lammatory cytokines, and K19-kras mice were transplanted with green fluorescent protein (GFP)–labeled arrow. Both H. felis infection and K-ras mutation induced upregulation of proinflammatory cytokines, sion of Dcamkl1 cells, and progression to oxyntic atrophy, metaplasia, hyperplasia, and high-grade dyspla9-kras transgenic mice uniquely displayedmucousmetaplasia as early as 3months and progressed to highdysplasia and invasive intramucosal carcinoma by 20months. In bonemarrow–transplanted K19-krasmice rogressed to dysplasia, a large proportion of stromal cells were GFP and bone marrow–derived, but only FP epithelial cells were observed. GFP bonemarrow–derived cells included leukocytes andCD45 stromal at expressed vimentin or α smooth muscle actin and were often found surrounding clusters of Dcamkl1 cells th cells at the base of gastric glands. In conclusion, the expression of mutant K-ras in K19 gastric epithelial cells can induce chronic inflammation and promote the development of dysplasia. Cancer Res; 70(21); 8435–45. ©2010 AACR.