Matondo, R. B.Toussaint, M. J. M.Govaert, K.M.Vuuren, L. D.Nantasanti, S.Nijkamp, M. W.Pandit, S. K.Tooten, P. C. J.Koster, M. H.Holleman, K.Schot, A.Gu, G.Spee, B.Roskams, T.Borel, R. I.Schotanus, B.Kranenburg, O.de Bruin, A.2018-10-092018-10-092016-08-23PMID: 27323406https://www.suaire.sua.ac.tz/handle/123456789/2616The 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.enLiverHCCHepatocyteHepatitisHepatectomyTumorRbp53Article