In situ nucleic acid detection of human telomerase in intrahepatic cholangiocarcinoma and its preneoplastic lesion.

Human telomerase, an enzyme associated with cellular immortality and tumorigenesis, is expressed by most malignant tumor cells. Human telomerase consists of human telomerase RNA (hTR) and telomerase protein components. One of the latter has been cloned and was termed telomerase-associated protein 1 (TP1). Using an in situ hybridization method, expression of hTR and TP1 mRNA was surveyed in 20 cases of intrahepatic cholangiocarcinoma (ICC) (5 of them were associated with hepatolithiasis), 5 cases of hepatolithiasis alone and 6 normal livers. Biliary dysplasia, which is suspected as a preneoplastic lesion of ICC, was found in the biliary tree in all 5 ICC cases with hepatolithiasis and in 1 of 5 cases of hepatolithiasis alone. Normal colonic mucosa was used as positive control. In 17 (85%) of 20 ICC cases, hTR and TP1 mRNA were detected in carcinoma cells. There was no correlation between histological subtype of ICC and expression of hTR and TP1 mRNA. Biliary dysplasia was also positive for both RNA. These signals were mainly located in the cytoplasm of carcinoma and dysplastic cells, especially around their nuclei. The signals were homogeneously detected in the carcinoma, while their distribution was more or less heterogeneous in the dysplastic foci. These signals were not detected in nondysplastic biliary epithelia in hepatolithiasis and normal livers. It seems likely that almost all ICC acquired telomerase activities irrespective of histological subtype and more importantly that cellular immortalization has already occurred in biliary dysplasia and this lesion is already involved in the malignant progression of ICC.