Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer.
OBJECTIVE
Hypergastrinemia occurs frequently in association with acid suppression and Helicobacter infection, but its role in the progression to gastric atrophy and gastric cancer has not been well defined.


METHODS
The effects of hypergastrinemia, and possible synergy with Helicobacter felis infection, were investigated in insulin-gastrin (INS-GAS) transgenic mice.


RESULTS
INS-GAS mice initially showed mild hypergastrinemia, increased maximal gastric acid secretion, and increased parietal cell number but later progressed to decreased parietal cell number and hypochlorhydria. Development of gastric atrophy was associated with increased expression of growth factors, heparin-binding epidermal growth factor and transforming growth factor alpha. At 20 months of age, INS-GAS mice showed no evidence of increased enterochromaffin-like cell number, but instead exhibited gastric metaplasia, dysplasia, carcinoma in situ, and gastric cancer with vascular invasion. Invasive gastric carcinoma was observed in 6 of 8 INS-GAS mice that were >20 months old. Helicobacter felis infection of INS-GAS mice led to accelerated (< or = 8 mo) development of intramucosal carcinoma (85%), with submucosal invasion (54%) and intravascular invasion (46%; P < or = 0.05).


CONCLUSIONS
These findings support the unexpected conclusion that chronic hypergastrinemia in mice can synergize with Helicobacter infection and contribute to eventual parietal cell loss and progression to gastric cancer.
Wang
T C
TC
Gastrointestinal Unit and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. wang@helix.mgh.harvard.edu
Dangler
C A
CA
Chen
D
D
Goldenring
J R
JR
Koh
T
T
Raychowdhury
R
R
Coffey
R J
RJ
Ito
S
S
Varro
A
A
Dockray
G J
GJ
Fox
J G
JG
D000818:Animals; D002452:Cell Count; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology; D005744:Gastric Acid / Q000378:metabolism; D005755:Gastrins / Q000097:blood*; D005757:Gastritis, Atrophic / Q000097:blood* / Q000382:microbiology; D016481:Helicobacter Infections / Q000097:blood*; D006493:Heparin / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006965:Hyperplasia; D006984:Hypertrophy; D036341:Intercellular Signaling Peptides and Proteins; D008679:Metaplasia; D051379:Mice; D008822:Mice, Transgenic; D013274:Stomach Neoplasms / Q000097:blood* / Q000382:microbiology* / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000378:metabolism
D005755:Gastrins; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D006493:Heparin