Apoptotic response to TGF-beta in fetal hepatocytes depends upon their state of differentiation

Transforming growth factor-beta (TGF-beta1) induces death of fetal hepatocytes by an apoptotic mechanism. However, even when very high concentrations and/or long-term exposure to the cytokine is used, 40-50% of cells always survive. The process of cell survival is coincident with changes in morphology and phenotype, with cells showing a fibroblastic appearance and eliciting an epithelial-fibroblastic transition. Surviving cells continue responding to TGF-beta in terms of growth control. Expression of liver-specific genes is very low in these cells; this effect is due to the decrease in their rate of transcription as soon as 2 h after the addition of the factor. Surviving cells present a decreased DNA binding activity for liver-enriched transcription factors, an increased DNA binding activity for AP-1, and a high expression of protooncogenes. These cells are immature hepatocytes since in the presence of the appropriate signal (i.e., epidermal growth factor), they can differentiate, organizing in cell clusters and increasing both liver-specific mRNA expression and liver-enriched transcription factor activity. In accord with these results, TGF-beta, secreted at high concentrations during liver carcinogenesis, might induce death of normal cells while providing a selective advantage for the survival of cells that are "partially transformed" or "less differentiated" and unresponsive to the factor.