CELLULAR-DISTRIBUTION OF TRANSCRIPTS FOR TISSUE INHIBITOR OF METALLOPROTEINASE-1 AND METALLOPROTEINASE-2 IN HUMAN HEPATOCELLULAR CARCINOMAS

The cellular distribution of tissue inhibitor of metalloproteinases (T IMP)-1, and TIMP-2 was studied by using in situ hybridization in surgi cally removed human hepatocellular carcinomas (HCCs) and cholangiocell ular carcinomas (CCCs). The purpose of this study was to characterize the potential involvement of TIMPs in the development of HCCs and CCCs . All HCCs and CCCs expressed TIMPs, The distribution of transcripts f or TIMPs in the tumors was mostly homogeneous, Expression of TIMPs in cancer cells was more intense than that in the surrounding noncancerou s liver (either, cirrhosis, chronic hepatitis, or normal), and express ion of TIMP-1 was stronger than that of TIMP-2. Expression of TIMPs va ried among HCC nodules, but there was no obvious association between t he expression level of TIMPs and differentiation stages or invasivenes s of the HCCs, Transcripts for TIMPs were clearly demonstrated in the metastatic HCC nodules in the lung. Expression of TIMP-1 in CCC was st rong, and small nodules of CCC were recognized in the liver. Immunohis tochemical study for TIMP-1 revealed a consistent staining of the TIMP -1 protein with the transcripts. In the peritumoral histologically nor mal liver, which was not infected with either hepatitis B or C virus, expression of TIMP-1 was found in various cell types, but that of TIMP -2 was weak. Expression of TIMP-1 in hepatocytes revealed clear zonal distribution, These results suggest that TIMPs may act on modulating t he matrix/tumor interaction and may play an important role in growth a nd invasion of HCCs and CCCs. Expression of TIMP-1 can be a marker of HCC metastasis to the lung, and also that of the extent of CCC invasio n. Furthermore, the consistent expression of TIMPs in many cell types of the noncancerous liver suggests some unknown functional role that m ust be clarified.