ROLE OF COPPER ACCUMULATION AND METALLOTHIONEIN INDUCTION IN SPONTANEOUS LIVER-CANCER DEVELOPMENT IN LEC RATS

The LEC rat spontaneously develops liver cancer after suffering chroni c liver injury caused by abnormal copper accumulation in the liver, bu t the role of copper accumulation in the induction of liver cancer rem ains obscure. We histochemically and biochemically examined the conten t of copper and metallothionein (MT), a cytoplasmic copper binding pro tein, in spontaneously developed preneoplastic and neoplastic liver le sions and compared them with those in the surrounding liver tissues. H istochemically, the majority of the preneoplastic liver lesions (68%) and liver cancers (59%) showed lower copper contents than the surround ing liver tissues and no lesions were shown to accumulate more copper than the surrounding tissues. A marked heterogeneity in copper stainin g was observed in cancer tissues. In contrast, these lesions showed an equal to higher MT content than their surroundings. Biochemical measu rements of copper and MT in cancer tissues supported the histochemical findings. The bromodeoxyuridine (BrdU) labeling index was high in all cancer tissues and some of the preneoplastic liver lesions, Parts of the cancer tissues with negative or weak staining for copper were high ly labeled with BrdU. Taking these results together, copper accumulati on may exert a growth inhibitory effect on surrounding hepatocytes, wh ereas the hepatocytes in the liver lesions could proliferate, escaping from the effect of copper toxicity by increasing their MT induction a nd lowering copper accumulation. Thus, accumulation of copper may act as a promoting factor for the development of liver cancer in LEC rats by creating a selective growth environment.