| First Author | Okumura T | Year | 2010 |
| Journal | Cancer Res | Volume | 70 |
| Issue | 21 | Pages | 8435-45 |
| PubMed ID | 20959488 | Mgi Jnum | J:165771 |
| Mgi Id | MGI:4838451 | Doi | 10.1158/0008-5472.CAN-10-1506 |
| Citation | Okumura T, et al. (2010) K-ras mutation targeted to gastric tissue progenitor cells results in chronic inflammation, an altered microenvironment, and progression to intraepithelial neoplasia. Cancer Res 70(21):8435-45 |
| abstractText | Chronic infectious diseases, such as Helicobacter pylori infection, can promote cancer in a large part through induction of chronic inflammation. Oncogenic K-ras mutation in epithelial cells activates inflammatory pathways, which could compensate for a lack of infectious stimulus. Gastric histopathology and putative progenitor markers [doublecortin and calcium/calmodulin-dependent protein kinase-like 1 (Dcamkl1) and keratin 19 (K19)] in K19-K-ras-V12 (K19-kras) transgenic mice were assessed at 3, 6, 12, and 18 months of age, in comparison with Helicobacter felis-infected wild-type littermates. Inflammation was evaluated by reverse transcription-PCR of proinflammatory cytokines, and K19-kras mice were transplanted with green fluorescent protein (GFP)-labeled bone marrow. Both H. felis infection and K-ras mutation induced upregulation of proinflammatory cytokines, expansion of Dcamkl1(+) cells, and progression to oxyntic atrophy, metaplasia, hyperplasia, and high-grade dysplasia. K19-kras transgenic mice uniquely displayed mucous metaplasia as early as 3 months and progressed to high-grade dysplasia and invasive intramucosal carcinoma by 20 months. In bone marrow-transplanted K19-kras mice that progressed to dysplasia, a large proportion of stromal cells were GFP(+) and bone marrow-derived, but only rare GFP(+) epithelial cells were observed. GFP(+) bone marrow-derived cells included leukocytes and CD45(-) stromal cells that expressed vimentin or alpha smooth muscle actin and were often found surrounding clusters of Dcamkl1(+) 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. |
