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K-ras mutation targeted to gastric tissue progenitor cells results in chronic inflammation, an altered microenvironment, and progression to intraepithelial neoplasia.
- Source :
-
Cancer research [Cancer Res] 2010 Nov 01; Vol. 70 (21), pp. 8435-45. Date of Electronic Publication: 2010 Oct 19. - Publication Year :
- 2010
-
Abstract
- 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 α 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.<br /> (©2010 AACR.)
- Subjects :
- Actins metabolism
Animals
Blotting, Western
Bone Marrow Transplantation
Carcinoma in Situ pathology
Cell Proliferation
Chemokines metabolism
Cytokines metabolism
Flow Cytometry
Fluorescent Antibody Technique
Gastric Mucosa metabolism
Helicobacter Infections metabolism
Helicobacter Infections pathology
Helicobacter Infections virology
Helicobacter felis
Humans
Hyperplasia etiology
Hyperplasia pathology
Hyperplasia virology
Immunoenzyme Techniques
In Situ Hybridization
Inflammation pathology
Keratin-19 genetics
Mesenchymal Stem Cells metabolism
Mesenchymal Stem Cells pathology
Metaplasia etiology
Metaplasia pathology
Metaplasia virology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Muscle, Smooth cytology
Muscle, Smooth metabolism
Neoplasm Invasiveness
Precancerous Conditions pathology
Proto-Oncogene Proteins p21(ras)
RNA, Messenger genetics
Reverse Transcriptase Polymerase Chain Reaction
Stem Cells metabolism
Stem Cells virology
Stomach pathology
Stomach virology
Stomach Neoplasms pathology
Stomach Neoplasms virology
Stromal Cells metabolism
Stromal Cells pathology
Stromal Cells virology
Carcinoma in Situ etiology
Inflammation etiology
Mutation genetics
Precancerous Conditions etiology
Proto-Oncogene Proteins physiology
Stem Cells pathology
Stomach Neoplasms etiology
ras Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 70
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 20959488
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-10-1506