Surgical resection and radiofrequency ablation initiate cancer in cytokeratin-19+-liver cells deficient for p53 and Rb
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Date
2016-08-23
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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.
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Keywords
Liver, HCC, Hepatocyte, Hepatitis, Hepatectomy, Tumor, Rb, p53