The long term prognosis of liver cancer patients remains unsatisfactory because of cancer recurrence after surgical interventions, particularly in patients with viral infections. Since hepatitis B and C viral proteins lead to inactivation of the tumor suppressors p53 and Retinoblastoma ( Rb), we hypothesize that surgery in the context of p53/Rb inactivation initiate de novo tumorigenesis.
We, therefore, generated transgenic mice with hepatocyte and cholangiocyte/ liver progenitor cell ( LPC)-specific deletion of p53 and Rb, by interbreeding conditional p53/Rb knockout mice with either Albumin-cre or Cytokeratin-19-cre transgenic mice.
We show that liver cancer develops at the necrotic injury site after surgical resection or radiofrequency ablation in p53/Rb deficient livers. Cancer initiation occurs as a result of specific migration, expansion and transformation of cytokeratin19(+)-liver ( CK-19(+)) cells. At the injury site migrating CK-19(+) cells formed small bile ducts and adjacent cells strongly expressed the transforming growth factor beta ( TGF beta). Isolated cytokeratin-19(+) cells deficient for p53/Rb were resistant against hypoxia and TGF beta-mediated growth inhibition. CK-19(+) specific deletion of p53/Rb verified that carcinomas at the injury site originates from cholangiocytes or liver progenitor cells.
These findings suggest that human liver patients with hepatitis B and C viral infection or with mutations for p53 and Rb are at high risk to develop tumors at the surgical intervention site.