Liver tumorigenesis by Helicobacter hepaticus: considerations of mechanism.
A new animal model for the causation of liver tumors via a bacterial infection presented itself fortuitously in the form of a new species, Helicobacter hepaticus. This species of Helicobacter colonizes the hepatic bile canaliculi in susceptible strains of mice, resulting in hepatitis and hepatocellular and hepatocholangiolar adenomas and carcinomas. The mechanism by which this infection leads to cancer is unknown. Tests with Helicobacter hepaticus have revealed thus far that the bacteria do not secrete a mutagen which is capable of detection by the Ames Assay. Measurement of oxidatively damaged bases in the liver DNA of hepaticus infected mice have shown accumulation of 8-oxodeoxyguanosine with disease progression. Other promutagenic DNA lesions, 7-methylguanine and O6-methylguanine, indicative of nitrosation of endogenous amines by nitric oxide, were not detected. Analysis of carcinomas and adenomas taken from H. hepaticus infected A/JCr mice revealed no mutations in ras oncogenes or in exons 5-8 of the p53 gene. These preliminary results indicate that a non-genotoxic tumor promotion mechanism, possibly implemented by reactive oxygen species from the immune response, is more likely than a genotoxic mechanism.
Canella
K A
KA
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, MD 21702-1201, USA.
Diwan
B A
BA
Gorelick
P L
PL
Donovan
P J
PJ
Sipowicz
M A
MA
Kasprzak
K S
KS
Weghorst
C M
CM
Snyderwine
E G
EG
Davis
C D
CD
Keefer
L K
LK
Kyrtopoulos
S A
SA
Hecht
S S
SS
Wang
M
M
Anderson
L M
LM
Rice
J M
JM
D000478:Alkylation; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D018736:DNA Adducts; D004249:DNA Damage; D016481:Helicobacter Infections / Q000150:complications*; D008113:Liver Neoplasms / Q000235:genetics / Q000382:microbiology*; D051379:Mice; D009154:Mutation; D018384:Oxidative Stress
D002273:Carcinogens; D018736:DNA Adducts