Host and microbial constituents influence Helicobacter pylori-induced cancer in a murine model of hypergastrinemia.
OBJECTIVE
Helicobacter pylori cag(+) strains and high-expression host interleukin 1beta (IL-1beta) polymorphisms augment the risk for intestinal-type gastric adenocarcinoma, a malignancy that predominates in males. We examined the effects of an H. pylori cancer-associated determinant (cagE), IL-1beta, and host gender in a transgenic hypergastrinemic (INS-GAS) murine model of gastric carcinogenesis.


METHODS
Male and female INS-GAS mice infected with wild-type H. pylori, an H. pylori cagE(-) mutant, or H. felis were killed 2-24 weeks postchallenge. Gastric injury was scored from 0 to 4, and mucosal IL-1beta levels were quantified by ELISA.


RESULTS
Male INS-GAS mice infected with H. pylori uniformly developed atrophy, intestinal metaplasia, and dysplasia by 6 weeks and carcinoma by 24 weeks. Mucosal IL-1beta concentrations increased 12 weeks following Helicobacter challenge, but levels then decreased by 24 weeks. Inactivation of cagE delayed the progression to carcinoma, but neoplasia ultimately developed in all males infected with the H. pylori mutant. In contrast, none of the H. pylori-infected female mice developed cancer, and injury scores, but not IL-1beta levels, were significantly higher in males compared with females.


CONCLUSIONS
H. pylori infection induces gastric adenocarcinoma in an experimental mouse model of disease. Cancer is restricted to males and loss of cagE temporally retards but does not abrogate pathologic progression. Mucosal levels of IL-1beta increase prior to the development of gastric cancer but are not related to gender. The INS-GAS model is effective for investigating discrete host-microbial interactions that culminate in gastric cancer within the context of biologic conditions induced by H. pylori.
Fox
James G
JG
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.
Wang
Timothy C
TC
Rogers
Arlin B
AB
Poutahidis
Theofilos
T
Ge
Zhongming
Z
Taylor
Nancy
N
Dangler
Charles A
CA
Israel
Dawn A
DA
Krishna
Uma
U
Gaus
Kristen
K
Peek
Richard M
RM
D000230:Adenocarcinoma / Q000209:etiology*; D000818:Animals; D001426:Bacterial Proteins / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005753:Gastric Mucosa / Q000473:pathology; D005755:Gastrins / Q000097:blood*; D016481:Helicobacter Infections / Q000150:complications*; D016480:Helicobacter pylori; D007375:Interleukin-1 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D011230:Precancerous Conditions / Q000209:etiology; D012737:Sex Factors; D013270:Stomach / Q000382:microbiology; D013274:Stomach Neoplasms / Q000209:etiology*
D001426:Bacterial Proteins; D005755:Gastrins; D007375:Interleukin-1; C103937:PicB protein, Helicobacter pylori