K-ras mutation targeted to gastric tissue progenitor cells results in chronic inflammation, an altered microenvironment, and progression to intraepithelial neoplasia.
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.
Division of Digestive and Liver Diseases, Columbia University Medical School, New York, New York, USA.
Tomoyuki
T
Okumura
Russell E
RE
Ericksen
Shigeo
S
Takaishi
Sophie S W
SS
Wang
Zinaida
Z
Dubeykovskiy
Wataru
W
Shibata
Kelly S
KS
Betz
Sureshkuma
S
Muthupalani
Arlin B
AB
Rogers
James G
JG
Fox
Anil K
AK
Rustgi
Timothy C
TC
Wang
D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D002278:Carcinoma in Situ / Q000209:etiology* / Q000473:pathology; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005753:Gastric Mucosa / Q000378:metabolism; D016481:Helicobacter Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology; D044922:Helicobacter felis; D006801:Humans; D006965:Hyperplasia / Q000209:etiology / Q000473:pathology / Q000821:virology; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D007249:Inflammation / Q000209:etiology* / Q000473:pathology; D053539:Keratin-19 / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D008679:Metaplasia / Q000209:etiology / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D011230:Precancerous Conditions / Q000209:etiology* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D013270:Stomach / Q000473:pathology / Q000821:virology; D013274:Stomach Neoplasms / Q000209:etiology* / Q000473:pathology / Q000821:virology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology; D018631:ras Proteins / Q000502:physiology*
D000199:Actins; D018925:Chemokines; D016207:Cytokines; C117307:KRAS protein, human; D053539:Keratin-19; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins