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Transforming Growth Factor ß as a Potent Promoter in Two-Stage BALB/c 3T3 Cell Transformation¹

International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France [E. H., F. K., H. Y.]; and the Friedrich-Miescher Lab. der Max-Planck-Gesellschaft, Tübingen, FRG [G. M., W. B.]

We have tested transforming growth factor ß (TGFß) in the two-stage BALB/c 3T3 cell transformation assay for possible tumor-promoting activity, since it has several effects similar to those of tumor-promoting phorbol esters. After initiation of BALB/c 3T3 cells with 3-methylcholanthrene, treatment with TGFß at 1 ng/ml alone or in combination with epidermal growth factor (EGF) for 4 weeks enhanced the number of transformed foci by 5- to 6-fold in comparison with uninitiated cells. Initiation treatment alone induced no or very few transformed foci in several assays. Treatment with phorbol-12,13-didecanoate (PDD) at 100 ng/ml for 4 weeks enhanced the number of transformed foci in initiated BALB/c 3T3 cells by 4- to 5-fold in comparison with uninitiated cells. Thus, TGFß at 1 ng/ml is as potent as PDD at 100 ng/ml for tumor-promoting activity in the two-stage BALB/c 3T3 cell transformation assay. The enhancing effect of TGFß was dose-related in the dose range tested (0.03–1 ng/ml) and was not reversible. Some of the foci induced by combined MCA-TGFß-EGF treatment were cloned, and eight out of nine clones tested produced tumors in nude mice. TGFß (1 ng/ml) plus EGF (2 ng/ml) increased the saturation density to a similar extent as PDD (100 ng/ml) but did not affect the growth of BALB/c 3T3 cells. We observed no change in junctional intercellular communication, as measured by the dye transfer method, when cells were treated with TGFß during the two-stage BALB/c 3T3 cell transformation assay. Nevertheless, there was selective communication between transformed and surrounding nontransformed cells; MCA-TGFß transformed cells intercommunicated among themselves but not with surrounding nontransformed cells. Our results indicate that TGFß has potent tumor-promoting activity in vitro, but that this activity is not mediated by a complete blockage of intercellular communication, as is suggested for phorbol ester tumor promoters.

¹ This work was supported by NCI Grant R01-CA40534.

² Fellow of the "Ligue Nationale Française Contre le Cancer" and then of the "Fondation Merieux."

³ To whom reprint requests should be addressed.

Received 10/21/87. Revised 2/10/88. Accepted 2/17/88.

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