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Apoptosis and proliferation in hepatocarcinogenesis related to cirrhosis
Author(s) -
Park Young Nyun,
Chae Kwang Jo,
Kim Young Bae,
Park Chanil,
Theise Neil
Publication year - 2001
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/1097-0142(20011201)92:11<2733::aid-cncr10126>3.0.co;2-5
Subject(s) - tunel assay , hccs , hepatocellular carcinoma , proliferating cell nuclear antigen , cirrhosis , terminal deoxynucleotidyl transferase , medicine , apoptosis , pathology , immunohistochemistry , cancer research , gastroenterology , biology , biochemistry
BACKGROUND Dysplastic nodules (DNs) recently have been identified as preneoplastic lesions of hepatocellular carcinoma (HCC). To test an alternative hypothesis regarding DN development, in which we have suggested that DNs develop as an infiltrating clonal expansion in advance of, or parallel to cirrhosis, the authors investigated the rates of apoptosis and proliferation in human hepatocarcinogenesis. METHODS The authors performed terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end labeling (TUNEL) assay and proliferation cell nuclear antigen (PCNA) staining in 11 low‐grade DNs, 8 high‐grade DNs including 3 cases with HCC subnodules, 10 small HCCs, and 29 cases of surrounding cirrhotic nodules. Hepatocellular carcinoma subnodules were present in three cases of high DNs. They determined TUNEL‐labeling indices (LIs) and PCNA‐LIs as the percentage of positive hepatocyte nuclei per 500 randomly counted cells. RESULTS TUNEL‐LIs (mean ± standard deviation) were 0.8 ± 0.82 in cirrhotic nodules, 1.0 ± 0.98 in low‐grade DNs, 3.0 ± 4.33 in high‐grade DNs, 8.7 ± 7.71 in HCC subnodules of high‐grade DNs, and 3.2 ± 3.58 in small HCCs. The peak values of apoptotic activity were higher in high‐grade DNs and HCCs than in low‐grade DNs and cirrhotic nodules. Each case of low‐grade DN showed a low to medium level of apoptotic activity when compared with those of the four surrounding cirrhotic nodules. The PCNA‐LIs were 2.6 ± 1.35 in cirrhotic nodules, 4.5 ± 2.31 in low‐grade DNs, 15.3 ± 10.50 in high‐grade DNs, 25.4 ± 5.25 in HCC subnodules of high‐grade DNs, and 34.9 ± 15.70 in small HCCs. The peak values gradually increased, although only HCC showed significantly elevated proliferation activity. The differences of PCNA‐LIs and TUNEL‐LIs, measured in each case, were 1.7 ± 1.89 in cirrhotic nodules, 3.6 ± 2.43 in low‐grade DNs, 7.9 ± 5.69 in high‐grade DNs, 16.2 ± 2.87 in HCC subnodules of high‐grade DNs, 28.2 ± 13.97 in small HCCs. At all stages of hepatocarcinogenesis, the rates of cell proliferation were higher than apoptosis, allowing a preferential net gain of (pre)neoplastic cells, and it was significantly increased in small HCCs. In regenerative cirrhotic nodules, 14% (4 cases) showed higher rates of apoptosis than proliferation. CONCLUSIONS The regulation/dysregulation of apoptosis of (pre)neoplastic cells as well as of proliferation may play an important role in the process of hepatocarcinogenesis. Cancer 2001;92:2733–8. © 2001 American Cancer Society.