Browsing by Author "Vuuren, L. D."

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Surgical resection and radiofrequency ablation initiate cancer in cytokeratin-19+-liver cells deficient for p53 and Rb
(2016-08-23) 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.
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.