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

Ramadhan B. Matondo, Mathilda J. M. Toussaint, Klaas M. Govaert, Luciel D. van Vuuren, Sathidpak Nantasanti, Maarten W. Nijkamp, Shusil K. Pandit, Peter C. J. Tooten, Mirjam H. Koster, Kaylee Holleman, Arend Schot, Guoqiang Gu, Bart Spee, Tania Roskams, Inne Borel Rinkes, Baukje Schotanus, Onno Kranenburg, Alain de Bruin*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

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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 cytokeratin19(+)-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 beta ( TGF beta). Isolated cytokeratin-19(+) cells deficient for p53/Rb were resistant against hypoxia and TGF beta-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.

    Original languageEnglish
    Pages (from-to)54662-54675
    Number of pages14
    JournalOncotarget
    Volume7
    Issue number34
    DOIs
    Publication statusPublished - 23-Aug-2016

    Keywords

    • liver
    • cholangiocytes
    • inflammation
    • necrosis
    • mice
    • HEPATOCELLULAR-CARCINOMA
    • GROWTH-FACTOR
    • TRANSCRIPTION FACTORS
    • STEM-CELLS
    • TUMOR
    • RECURRENCE
    • EXPRESSION
    • REGENERATION
    • HEPATECTOMY
    • MOUSE

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