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 oftumor growth. The cytokine-driven modulation of tumor growth wasinvestigated during the progression of a hepatocellular carcinoma (HCC) inSV40 large T tumor antigen transgenic mice. In vivo, an increased rate ofliver growth correlated with increased transforming growth factor(TGF)-beta 1 mRNA expression, while the greatest amounts of tumor necrosisfactor (TNF)-alpha mRNA were detected earlier during tumor development.Conversely, no particular alteration of IL-1 alpha, IL-1 beta, IL-6, IL-2,IL-4 and IFN-gamma mRNA production could be reported. In vitro,hepatocyte-like tumor cell lines established at two stages, either beforeor after HCC differentiation, were characterized. The early-stage-derivedcell line produced TNF-alpha mRNA, but had barely detectable expression ofTGF-beta 1 mRNA, while later-stage- derived cell lines showed thereciprocal pattern. All cell lines displayed a lack of sensitivity toTNF-alpha, although some degree of sensitivity to TNF-alpha could beobserved in the presence of actinomycin-D or after treatment withIFN-gamma. The early-stage- derived cell line was sensitive to the growthinhibitory effects of TGF- beta 1, but late-stage-derived tumor cell linesdisplayed a loss of sensitivity to TGF-beta 1 which correlated with theincreased expression of TGF-beta 1 mRNA. Altogether, this suggests thattumor cells contribute to the discrete TNF-alpha and TGF-beta 1 expressionpatterns during HCC progression. This model of HCC could be of valuableinterest to assess the impact of various immunotherapeutic strategies onmodulation of tumor growth.