Compensatory apoptosis in response to SV40 large T antigen expression in the liver.
Transgenesis allows the in vivo determination of the effects of oncogene expression in normal tissues. In an attempt to understand the mechanism underlying liver transformation, we have previously created transgenic mice carrying the SV40 early gene sequences, which developed hepatocarcinoma in a reproducible way. In the present study, we show that constant expression of the transgene was directly correlated to an abnormally increased hepatocyte proliferation, even at the adult stage. We further demonstrate in this model that the preneoplastic stage of hepatocarcinoma is characterized by marked ploidy alterations as early as 1 month, including the emergence of aneuploid and hyperpolyploid cells, and the persistence of an important diploid cell population. We show that this elevated proliferation is early and transiently counterbalanced by a mechanism of apoptosis, which maintains liver homeostasis. The disappearance of this programmed cell death response effective during preneoplasia might signal the commitment of the liver to neoplasia.
INSERM U-380, Institut Cochin de Génétique Moléculaire, Paris, France.
I
I
Allemand
G
G
Grimber
M
M
Kornprobst
M
M
Bennoun
T
T
Molina
P
P
Briand
V
V
Joulin
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology*; D017209:Apoptosis; D016161:Genes, Retinoblastoma / Q000502:physiology; D016158:Genes, p53 / Q000502:physiology; D008099:Liver / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000473:pathology*; D013539:Simian virus 40 / Q000276:immunology*
D000952:Antigens, Polyomavirus Transforming