INHERENT INCREASE OF APOPTOSIS IN LIVER-TUMORS - IMPLICATIONS FOR CARCINOGENESIS AND TUMOR-REGRESSION

We quantitatively assessed rates of cell replication and of apoptosis during the development and regression of liver cancer. In rats, apopto tic activity gradually increased from normal liver to putative preneop lastic foci (PPF), to hepatocellular adenoma (HCA), and to hepatocellu lar carcinoma (HCC). At all stages, rates of cell replication were hig her than of apoptosis, allowing a preferential net gain of (pre)neopla stic cells. As in rats, in human HCC, birth and death rates were incre ased manifold, indicating a species independent phenomenon. Implicatio ns of the increasing cell turnover were studied in rats using the admi nistration and withdrawal of nafenopin (NAF), a liver mitogen and nong enotoxic carcinogen. Prolonged NAF treatment enhanced cell number in n ormal liver by 25%, while PPF and liver tumors were amplified at least 100-fold. After stopping NAF treatment, cell replication ceased, whil e cell elimination by apoptosis was increased in normal and (pre)neopl astic liver. HCA and HCC showed the most pronounced shifts from replic ation toward apoptosis. As a result, 5 weeks after halting NAF, 20% of cells in normal liver, but about 85% of (pre)neoplastic lesions inclu ding HCC, were eliminated. The implications of these findings include that nongenotoxic carcinogens can act as survival factors even for mal ignant cells. Furthermore, tumor cells not only exhibit excessive prol iferation, but also undergo apoptosis at rates that far exceed those i n normal tissue. Therefore, inhibition of cell death by the survival a ctivity of nongenotoxic carcinogens results in selective growth of (pr e)neoplastic lesions. On the other hand, blockade of survival effects leads to excessive apoptosis in (pre)neoplasia and seems promising as a therapeutic concept for the selective elimination of (liver) cancer.