Surgical resection and radiofrequency ablation initiate cancer in cytokeratin-19+- liver cells deficient for p53 and Rb
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Ramadhan B. Matondo1,*, Mathilda J.M. Toussaint1,*, Klaas M. Govaert2, Luciel D. van Vuuren1, Sathidpak Nantasanti1,4, Maarten W. Nijkamp2, Shusil K. Pandit1, Peter C.J. Tooten1, Mirjam H. Koster1, Kaylee Holleman1,4, Arend Schot1, Guoqiang Gu3, Bart Spee4, Tania Roskams5, Inne Borel Rinkes2, Baukje Schotanus4, Onno Kranenburg2, Alain de Bruin1,6
1Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
2Department of Surgical Oncology, Cancer Centre, UMC Utrecht, Utrecht, The Netherlands
3Program in Developmental Biology and the Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA
4Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
5Translational Cell and Tissue Research, University of Leuven, Leuven, Belgium
6Department of Pediatrics, Division of Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
*These authors contributed equally to this work
Alain de Bruin, email: [email protected]
Keywords: liver, cholangiocytes, inflammation, necrosis, mice
Received: December 04, 2015 Accepted: May 28, 2016 Published: June 13, 2016
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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