COMPENSATORY APOPTOSIS IN RESPONSE TO SV40 LARGE T-ANTIGEN EXPRESSIONIN THE LIVER

Transgenesis allows the in vivo determination of the effects of oncoge ne expression in normal tissues, In an attempt to understand the mecha nism underlying liver transformation, we had previously created transg enic mice carrying the SV40 early gene sequences, which developed hepa tocarcinoma in a reproducible way, In the present study, we show that constant expression of the transgene was directly correlated to an abn ormally increased hepatocyte proliferation, even at the adult stage, W e further demonstrate in this model that the preneoplastic stage of he patocarcinoma is characterized by marked ploidy alterations as early a s 1 month, including the emergence of aneuploid and hyperpolyploid cel ls, and the persistence of an important diploid cell population, We sh ow that this elevated proliferation is early and transiently counterba lanced by a mechanism of apoptosis, which maintains liver homeostasis. The disappearance of this programmed cell death response effective du ring preneoplasia might signal the commitment of the liver to neoplasi a.