Critical stages of tumor growth regulation in transgenic mice harboring a hepatocellular carcinoma revealed by distinct patterns of tumor necrosis factor-α and transforming growth factor-β mRNA production

There is now good evidence that cytokines contribute to the regulation of tumor growth. The cytokinedriven modulation of tumor growth was investigated during the progression of a hepatocellular carcinoma (HCC) in SV40 large T tumor antigen transgenic mice. In vivo, an increased rate of liver growth correlated with increased transforming growth factor (TGF)-β1 mRNA expression, while the greatest amounts of tumor necrosis factor (TNF)-α mRNA were detected earlier during tumor development. Conversely, no particular alteration of IL-1α, IL-1β, IL-6, IL-2, IL-4 and IFN-γ mRNA production could be reported. In vitro, hepatocyte-like tumor cell lines established at two stages, either before or after HCC differentiation, were characterized. The early-stage-derived cell line produced TNF-α mRNA, but had barely detectable expression of TGF-β1 mRNA, while later-stagederived cell lines showed the reciprocal pattern. All cell lines displayed a lack of sensitivity to TNF-α, although some degree of sensitivity to TNF-α could be observed in the presence of actinomycin-D or after treatment with IFN-γ. The early-stage-derived cell line was sensitive to the growth inhibitory effects of TGF-β1, but late-stage-derived tumor cell lines displayed a loss of sensitivity to TGF-β1 which correlated with the increased expression of TGF-β1 mRNA. Altogether, this suggests that tumor cells contribute to the discrete TNF-α and TGF-β1 expression patterns during HCC progression. This model of HCC could be of valuable interest to assess the impact of various immunotherapeutic strategies on modulation of tumor growth.