Abstract
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 cytokeratin-19+-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 β (TGFβ). Isolated cytokeratin-19+ cells deficient for p53/Rb were resistant against hypoxia and TGFβ-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.
Highlights
Liver cancer is one of the deadliest forms of cancer with approximately 700,000 deaths per year worldwide [1]
LacZ expression was observed in liver tumors 10 weeks after radiofrequency ablation (RFA), and we found that undifferentiated carcinomas cells and cholangiocytes/ liver progenitor cell (LPC) expressed LacZ, supporting that undifferentiated neoplastic cells originate from epithelial liver cells (Figure 4F)
An important question, which is difficult to address in human patients, is whether liver cancers originate from hepatocytes, liver progenitor cells or cholangiocytes
Summary
Liver cancer is one of the deadliest forms of cancer with approximately 700,000 deaths per year worldwide [1]. Hepatic resection and radiofrequency ablation (RFA) are the treatment of choice, especially for patients with tumors associated with early and severe cirrhosis respectively [2, 3]. Many risk factors have been associated with liver cancer including chronic hepatitis B and C viral infection, and basically all cirrhosis-inducing conditions [7]. These etiological exposures are believed to interfere with the cell cycle machinery through inactivating tumor suppressor pathways [8]. Liver-specific deletion of both p53 and Rb did not result in spontaneous liver cancer in mice aged to one year. In response to diethylnitrosamine (DEN), tumors started to develop at the age of three months [17, 18]
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