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

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dc.creatorMatondo, R. B.
dc.creatorToussaint, M. J. M.
dc.creatorGovaert, K.M.
dc.creatorVuuren, L. D.
dc.creatorNantasanti, S.
dc.creatorNijkamp, M. W.
dc.creatorPandit, S. K.
dc.creatorTooten, P. C. J.
dc.creatorKoster, M. H.
dc.creatorHolleman, K.
dc.creatorSchot, A.
dc.creatorGu, G.
dc.creatorSpee, B.
dc.creatorRoskams, T.
dc.creatorBorel, R. I.
dc.creatorSchotanus, B.
dc.creatorKranenburg, O.
dc.creatorde Bruin, A.
dc.date2018-10-09T06:23:14Z
dc.date2018-10-09T06:23:14Z
dc.date2016-08-23
dc.date.accessioned2022-10-25T08:50:41Z
dc.date.available2022-10-25T08:50:41Z
dc.descriptionThe 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.
dc.descriptionNFP grant : R.B.M., DU.282001.1.3
dc.formatapplication/pdf
dc.identifierPMID: 27323406
dc.identifierhttps://www.suaire.sua.ac.tz/handle/123456789/2616
dc.identifier.urihttp://hdl.handle.net/123456789/90510
dc.languageen
dc.subjectLiver
dc.subjectHCC
dc.subjectHepatocyte
dc.subjectHepatitis
dc.subjectHepatectomy
dc.subjectTumor
dc.subjectRb
dc.subjectp53
dc.titleSurgical resection and radiofrequency ablation initiate cancer in cytokeratin-19+-liver cells deficient for p53 and Rb
dc.typeArticle

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