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Mitogenic and Antimitogenic Transforming Growth Factors Secreted by Adenovirus 2- and Simian Virus 40-transformed Hamster Cells: Possible Roles in Promoting Tumorigenesis

Section on Viruses and Cellular Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda Maryland 20892

Adenovirus 2 (Ad2)- and simian virus 40 (SV40)-transformed hamster embryo cells differ markedly in a number of phenotypic properties including their potential for inducing tumors in hamsters. Both Ad2- and SV40-transformed cells are immortalized and readily induce tumors in immunoincompetent newborn syngeneic hamsters, but only SV40-transformed cells are highly oncogenic in both adult syngeneic and allogeneic immunocompetent hamsters. The reasons for the difference in the oncogenic potential of the Ad2- and SV40-transformed phenotypes remain elusive. However, recent studies with transforming growth factors (TGFs) indicate that these factors play an important role in determining many phenotypic characteristics of transformed cells. To determine whether TGFs secreted by Ad2- and SV40-transformed hamster embryo cells differ, we have examined the ability of media conditioned by these two transformed cell phenotypes to modulate thymidine uptake in quiescent, untransformed cells. We found that both transformed phenotypes secrete very similar TGF-like mitogenic factors which inhibit binding of ¹²⁵I-labeled epidermal growth factor to its receptor. Our results also show that SV40-transformed cells, but not Ad2-transformed cells, secrete a powerful mitogenic inhibitor (MI). The MI secreted by SV40-transformed cells is inhibitory for several transformed and untransformed cell types and exerts a cytostatic, not cytolytic, action on untransformed primary hamster embryo cells. MI elutes from size exclusion high-performance liquid chromatography columns with a molecular weight of 24,000. Although MI has about the same molecular weight as TGFß, it differs from TGFß in two important respects: it is heat labile and it has a different target specificity for antimitogenic activity. The MI secreted by SV40-transformed cells also inhibits thymidine uptake by concanavalin A-stimulated spleen lymphocytes. This finding suggests that MI might contribute to the extreme oncogenicity of SV40-transformed cells by inhibiting mobilization of immune effector cells at the site of tumor cell proliferation.

¹ To whom requests for reprints should be addressed.

Received 10/ 2/86. Revised 2/17/87. Revised 4/23/87. Accepted 4/30/87.