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 MESSENGER-RNAPRODUCTION

There is now good evidence that cytokines contribute to the regulation of tumor growth, The cytokine-driven modulation of tumor growth was i nvestigated 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 fac tor (TGF)-beta 1 mRNA expression, while the greatest amounts of tumor necrosis factor (TNF)-alpha mRNA were detected earlier during tumor de velopment, Conversely, no particular alteration of IL-1 alpha, IL-1 be ta, 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 before or after HCC differentiation, were characterized, The ea rly-stage-derived cell line produced TNF-alpha mRNA, but had barely de tectable expression of TGF-beta 1 mRNA, while later-stage-derived cell lines showed the reciprocal pattern, All cell lines displayed a lack of sensitivity to TNF-alpha, although some degree of sensitivity to TN F-alpha could be observed in the presence of actinomycin-D or after tr eatment with IFN-gamma. The early-stage-derived cell line was sensitiv e to the growth inhibitory effects of TGF-beta 1, but late-stage-deriv ed tumor cell lines displayed a loss of sensitivity to TGF-beta 1 whic h correlated with the increased expression of TGF-beta 1 mRNA, Altoget her, this suggests that tumor cells contribute to the discrete TNF-alp ha and TGF-beta 1 expression patterns during HCC progression, This mod el of HCC could be of valuable interest to assess the impact of variou s immunotherapeutic strategies on modulation of tumor growth.