Reduced autophagic activity in primary rat hepatocellular carcinoma and ascites hepatoma cells.

Autophagy, measured as the sequestration of an endogenous cytosolic enzyme (LDH), showed a progressive rate reduction during diethylnitrosamine-induced rat liver carcinogenesis. In primary hepatocellular carcinomas the autophagic activity was only one-fourth of that seen in normal hepatocytes. Reduced autophagy was also observed in peritumorous hepatocytes and in cells from preneoplastic liver, and a complete suppression of autophagic protein degradation was seen in normal hepatocytes treated with ascitic fluid from an ascites hepatoma, suggesting that tumour cells and their precursors may produce autophagy-suppressive factors with an autocrine and paracrine action. In cells from the transplantable rat ascites hepatoma, Yoshida AH-130, autophagic activity was negligible during active (logarithmic) growth, but increased to approximately 0.4%/h at high cell density, i.e. in stationary phase. In contrast to normal hepatocytes, autophagy in the AH-130 cells was not inhibited by ascitic fluid. The hepatoma cells would thus appear to have lost some aspects of autophagy regulation while retaining others. However, even the highest rate of hepatoma cell autophagy was only one-tenth of the maximal activity seen in normal hepatocytes, confirming the hypothesis that reduced autophagy may be an important aspect of growth deregulation in liver cancer.