Development of a rat model for orthotopic liver transplantation for hepatocellular carcinoma

Abstract

Surgical resection is of limited benefit in hepatocellular carcinoma accompanied by severe liver cirrhosis or multicentric hepatic cancer. The long-term survival of patients with advanced hepatocellular carcinoma after transplantation is quite poor. We have studied the characteristics, natural course, and cause of diethylnitrosamine-induced liver cancer in rats and have shown it to be a good model of liver cancer in human beings. Therefore we performed orthotopic liver transplantation (OLT) in rats with diethylnitrosamine-induced liver cancer to study the patterns of recurrence. Diethylnitrosamine 100 parts per million in drinking water was administered daily for 4 months to male inbred LEW rats. A laparotomy was performed 120 or 134 days after commencing the oral diethylnitrosamine to confirm the induction of cancer confined grossly to the liver. The livers were resected, and orthotopic transplantation with livers of normal LEW rats was performed. By day 150 all the rats in the non-OLT group died of intraabdominal hemorrhage caused by spontaneous rupture of liver cancer (mean survival time +/- SD, 138.2 +/- 5.3 days; n = 14). However, the OLT (day 120) group recovered their body weight comparatively early after transplantation and survived a maximum of 218 days until death from recurrence (203.8 +/- 21.3 days; n = 4). A significant extension in survival time was observed (p < 0.01). In autopsies performed at the time of death, metastatic liver cancer was observed in the transplanted livers with two showing metastases to the lung. The cause of death was cancer in all the rats. However, the OLT (day 134) group all died of major complications of severe pneumonia and disseminated intravascular coagulation within 2 weeks of OLT (141.3 +/- 5.0 days; n = 4). After liver transplantation to rats with hepatocellular cancer confined to the liver, recurrence was observed at a comparatively early stage in all transplant recipients. Although a significant prolongation of survival was noted, they all died of cancer. The timing of transplantation is also an important factor. This experimental liver transplantation model of progressive rat liver cancer will be useful in the study of primary liver cancer in human beings.