Surgical resection and radiofrequency ablation initiate cancer in cytokeratin-19+- liver cells deficient for p53 and Rb.
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.
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Ramadhan B
RB
Matondo
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Mathilda Jm
MJ
Toussaint
Department of Surgical Oncology, Cancer Centre, UMC Utrecht, Utrecht, The Netherlands.
Klaas M
KM
Govaert
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Luciel D
LD
van Vuuren
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.|Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Sathidpak
S
Nantasanti
Department of Surgical Oncology, Cancer Centre, UMC Utrecht, Utrecht, The Netherlands.
Maarten W
MW
Nijkamp
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Shusil K
SK
Pandit
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Peter Cj
PC
Tooten
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Mirjam H
MH
Koster
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.|Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Kaylee
K
Holleman
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Arend
A
Schot
Program in Developmental Biology and the Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
Guoqiang
G
Gu
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Bart
B
Spee
Translational Cell and Tissue Research, University of Leuven, Leuven, Belgium.
Tania
T
Roskams
Department of Surgical Oncology, Cancer Centre, UMC Utrecht, Utrecht, The Netherlands.
Inne Borel
IB
Rinkes
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Baukje
B
Schotanus
Department of Surgical Oncology, Cancer Centre, UMC Utrecht, Utrecht, The Netherlands.
Onno
O
Kranenburg
Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.|Department of Pediatrics, Division of Molecular Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Alain
A
de Bruin
D000818:Animals; D017115:Catheter Ablation / Q000009:adverse effects / Q000379:methods; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D006498:Hepatectomy / Q000009:adverse effects / Q000379:methods; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D053539:Keratin-19 / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics*; D046509:Tissue Culture Techniques; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
D053539:Keratin-19; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53
cholangiocytes; inflammation; liver; mice; necrosis