K-ras gene mutations in intrahepatic bile duct tumors of Syrian golden hamsters.
OBJECTIVE
In our laboratory, we have developed a new model of carcinoma of the bile duct in Syrian golden hamsters, using N-nitrosobis(2-oxopropyl)amine (BOP). Morphologic and biologic characteristics of the carcinoma induced in this model are similar to those seen in humans. In order to examine the gene-related carcinogenesis of intrahepatic bile duct carcinoma, we investigated mutations in the K-ras gene in various early hyperplastic and neoplastic lesions of these hamsters, according to the original sites of the lesions.


METHODS
Inbred female hamsters were given a subcutaneous injection of N-nitrosobis(2-oxopropyl)amine (BOP) following dissection of the extrahepatic bile duct on the distal end of the common duct and preparation of a cholecystoduodenostomy (CDDB) or simple laparotomy (SL). Neoplastic lesions arising from the intrahepatic bile duct were histologically examined, and K-ras mutations were investigated.


RESULTS
Mutations of K-ras codon 12 were evident in 12% of tubular hyperplasias, 19% of tubular adenocarcinomas, 15% of papillary hyperplasias and 36% of papillary adenocarcinomas. In papillary adenocarcinoma arising from a large bile duct, K-ras mutations occurred more frequently than in tubular adenocarcinoma arising from ductule or ductular proliferation. K-ras mutations were present even in a hyperplasia; the positive rates of the mutations increased in the presence of a carcinoma. Genetic changes in carcinoma of the intrahepatic bile duct varied based on sites of the duct and the histological type.


CONCLUSIONS
A part of the hyperplastic lesions of the intrahepatic bile duct presented K-ras gene mutation. This suggests that K-ras gene mutation is an early event in the carcinogenic process. In carcinoma of the intrahepatic bile duct, the lesion arising from a large bile duct of the hepatic hilum tended to exhibit a higher frequency of K-ras gene mutation than did a tubular lesion arising from ductule or ductal proliferation. This hamster model is useful to examine the carcinogenesis of human intrahepatic bile duct carcinoma.
Yamanaka
S
S
Department of Surgery II, Nagasaki University School of Medicine, Japan.
Tomioka
T
T
Tajima
Y
Y
Okada
K
K
Shiku
H
H
Kanematsu
T
T
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics*; D000231:Adenocarcinoma, Papillary / Q000139:chemically induced / Q000235:genetics; D000818:Animals; D001650:Bile Duct Neoplasms / Q000139:chemically induced / Q000235:genetics*; D001653:Bile Ducts, Intrahepatic; D002273:Carcinogens; D006224:Cricetinae; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D008647:Mesocricetus; D009154:Mutation; D009602:Nitrosamines
D002273:Carcinogens; D009602:Nitrosamines; C013622:nitrosobis(2-oxopropyl)amine