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EBV-inducing factor/transforming growth factor type beta (EIF/TGF-beta) exhibits tumor-promoting activity for C3H-10T1/2 mouse fibroblasts in vitro. Treatment of C3H 10 T 1/2 fibroblasts seeded at low density with initiating doses of UV light, followed by culture in the presence of EIF/TGF-beta leads to the appearance of foci of stably transformed cells that have the potential to grow in soft agar. The promoting effect depends both on the dose of EIF/TGF-beta applied and its continuous presence for 2 to 3 weeks. In addition to its procarcinogenic effect in tumor promotion, EIF/TGF-beta exhibits a strong negative effect on transformed cells surrounded by normal cells, indicating a dual role of EIF/TGF-beta in carcinogenesis. The lack of completely transformed individual cells in the initiated cell population and the negative effect of EIF/TGF-beta on transformed cells in contact with normal cells exclude any possible explanation of the tumor-promoting effect of EIF/TGF-beta as being the result of a selection process due to the establishment of growth advantages for cells transformed by the initiator. The data, in fact, indicate that tumor promotion by EIF/TGF-beta implies the stable acquisition of distinct qualitative changes by the cells.

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Studies on the mechanisms of transformation of mammalian cells by herpes simplex virus (HSV) in vitro have been prevented so far by the extremely low transformation frequencies obtained in monolayer culture. Here we present a transformation system that relies on the direct seeding in soft agar of infected single cells, thus avoiding negative interactions between normal and transformed cells. We took advantage of HSV-I temperature-sensitive mutants at the UL9 locus, which codes for a DNA-binding protein necessary for viral DNA replication. At the non-permissive temperature, viral DNA synthesis and late gene expression are prevented. Viral gene expression is restricted to immediate early and early genes. Induction of transformation was highly efficient in our one-step transformation system. It depended on intact viral particles and viral DNA. Immediate early and/or early viral gene expression was sufficient to induce transformation. Colonies were stably transformed and did not show any rescue of viable virus after temperature downshift and co-cultivation with susceptible cells. Transformed cells maintained the transformed state in the absence of viral DNA. Our data therefore support the "hit-and-run" hypothesis for the transforming effect of HSV.