Critical stages of tumor growth regulation in transgenic mice harboring a hepatocellular carcinoma revealed by distinct patterns of tumor necrosis factor-alpha and transforming growth factor-beta 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)-b1 mRNA expression, while the greatest amounts of tumor necrosis factor (TNF)-a mRNA were detected earlier during tumor development. Conversely, no particular alteration of IL-1a, IL-1b, IL-6, IL-2, IL-4 and IFN-g 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-a mRNA, but had barely detectable expression of TGF-b1 mRNA, while later-stagederived cell lines showed the reciprocal pattern. All cell lines displayed a lack of sensitivity to TNF-a, although some degree of sensitivity to TNF-a could be observed in the presence of actinomycin-D or after treatment with IFN-g. The early-stage-derived cell line was sensitive to the growth inhibitory effects of TGF-b1, but late-stage-derived tumor cell lines displayed a loss of sensitivity to TGF-b1 which correlated with the increased expression of TGF-b1 mRNA. Altogether, this suggests that tumor cells contribute to the discrete TNF-a and TGF-b1 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.