PMID- 20959488
OWN - NLM
STAT- MEDLINE
DCOM- 20101221
LR  - 20220331
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 70
IP  - 21
DP  - 2010 Nov 1
TI  - K-ras mutation targeted to gastric tissue progenitor cells results in chronic 
      inflammation, an altered microenvironment, and progression to intraepithelial 
      neoplasia.
PG  - 8435-45
LID - 10.1158/0008-5472.CAN-10-1506 [doi]
AB  - 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.
CI  - (c)2010 AACR.
FAU - Okumura, Tomoyuki
AU  - Okumura T
AD  - Division of Digestive and Liver Diseases, Columbia University Medical School, New 
      York, New York, USA.
FAU - Ericksen, Russell E
AU  - Ericksen RE
FAU - Takaishi, Shigeo
AU  - Takaishi S
FAU - Wang, Sophie S W
AU  - Wang SS
FAU - Dubeykovskiy, Zinaida
AU  - Dubeykovskiy Z
FAU - Shibata, Wataru
AU  - Shibata W
FAU - Betz, Kelly S
AU  - Betz KS
FAU - Muthupalani, Sureshkuma
AU  - Muthupalani S
FAU - Rogers, Arlin B
AU  - Rogers AB
FAU - Fox, James G
AU  - Fox JG
FAU - Rustgi, Anil K
AU  - Rustgi AK
FAU - Wang, Timothy C
AU  - Wang TC
LA  - eng
GR  - R01 CA093405/CA/NCI NIH HHS/United States
GR  - U54 CA126513/CA/NCI NIH HHS/United States
GR  - P30 DK050306/DK/NIDDK NIH HHS/United States
GR  - P30 ES002109/ES/NIEHS NIH HHS/United States
GR  - R01 CA120979/CA/NCI NIH HHS/United States
GR  - R01 DK060694/DK/NIDDK NIH HHS/United States
GR  - U01 CA143056/CA/NCI NIH HHS/United States
GR  - 5R01 CA120979-02/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20101019
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Actins)
RN  - 0 (Chemokines)
RN  - 0 (Cytokines)
RN  - 0 (KRAS protein, human)
RN  - 0 (Keratin-19)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Messenger)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - Blotting, Western
MH  - Bone Marrow Transplantation
MH  - Carcinoma in Situ/*etiology/pathology
MH  - Cell Proliferation
MH  - Chemokines/metabolism
MH  - Cytokines/metabolism
MH  - Flow Cytometry
MH  - Fluorescent Antibody Technique
MH  - Gastric Mucosa/metabolism
MH  - Helicobacter Infections/metabolism/pathology/virology
MH  - Helicobacter felis
MH  - Humans
MH  - Hyperplasia/etiology/pathology/virology
MH  - Immunoenzyme Techniques
MH  - In Situ Hybridization
MH  - Inflammation/*etiology/pathology
MH  - Keratin-19/genetics
MH  - Mesenchymal Stem Cells/metabolism/pathology
MH  - Metaplasia/etiology/pathology/virology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Muscle, Smooth/cytology/metabolism
MH  - Mutation/*genetics
MH  - Neoplasm Invasiveness
MH  - Precancerous Conditions/*etiology/pathology
MH  - Proto-Oncogene Proteins/*physiology
MH  - Proto-Oncogene Proteins p21(ras)
MH  - RNA, Messenger/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Stem Cells/metabolism/*pathology/virology
MH  - Stomach/pathology/virology
MH  - Stomach Neoplasms/*etiology/pathology/virology
MH  - Stromal Cells/metabolism/pathology/virology
MH  - ras Proteins/*physiology
PMC - PMC2970750
MID - NIHMS236226
EDAT- 2010/10/21 06:00
MHDA- 2010/12/22 06:00
PMCR- 2011/11/01
CRDT- 2010/10/21 06:00
PHST- 2010/10/21 06:00 [entrez]
PHST- 2010/10/21 06:00 [pubmed]
PHST- 2010/12/22 06:00 [medline]
PHST- 2011/11/01 00:00 [pmc-release]
AID - 0008-5472.CAN-10-1506 [pii]
AID - 10.1158/0008-5472.CAN-10-1506 [doi]
PST - ppublish
SO  - Cancer Res. 2010 Nov 1;70(21):8435-45. doi: 10.1158/0008-5472.CAN-10-1506. Epub 
      2010 Oct 19.