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, apoptotic activity gradually increased from normal liver to putative preneoplastic foci (PPF), to hepatocellular adenoma (HCA), and to hepatocellular carcinoma (HCC). At all stages, rates of cell replication were higher than of apoptosis, allowing a preferential net gain of (pre)neoplastic cells. As in rats, in human HCC, birth and death rates were increased manifold, indicating a species-independent phenomenon. Implications of the increasing cell turnover were studied in rats using the administration and withdrawal of nafenopin (NAF), a liver mitogen and nongenotoxic carcinogen. Prolonged NAF treatment enhanced cell number in normal liver by 25%, while PPF and liver tumors were amplified at least 100-fold. After stopping NAF treatment, cell replication ceased, while cell elimination by apoptosis was increased in normal and (pre)neoplastic liver. HCA and HCC showed the most pronounced shifts from replication toward apoptosis. As a result, 5 weeks after halting NAF, 20% of cells in normal liver, but about 85% of (pre)neoplastic lesions including HCC, were eliminated. The implications of these findings include that nongenotoxic carcinogens can act as survival factors even for malignant cells. Furthermore, tumor cells not only exhibit excessive proliferation, but also undergo apoptosis at rates that far exceed those in normal tissue. Therefore, inhibition of cell death by the survival activity of nongenotoxic carcinogens results in selective growth of (pre)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.