We have earlier shown that Syrian hamster cells spontaneously transformed in vitro during in vivo progression, acquire in 1 step, along with highly increased tumorigenicity, 2 new properties characterizing the [H2O2CA + tPGE(S)] phenotype, i.e., a high H2O2 catabolizing (antioxidant) activity and the ability to release PGE2 upon contact with NK cells. In contrast, RSV-SR-(v-src)-transformed cells acquire the [H2O2CA + PGE(S)] phenotype and high tumorigenicity during in vitro transformation, i.e., without preliminary in vivo selection. In the present study, the possible influence of different transforming genes on the rates of subsequent in vivo tumor progression was studied using cells in vitro transformed by SV40, BAV-3, or transduced by activated genes Ha-ras, p53, myc and bcl-2. The expression of the [H2O2CA + PGE(S)] phenotype, the extent of tumorigenic and spontaneous metastasizing activities were examined before and during in vivo cells selection in s.c. growing tumors. Our results demonstrate that: (1) after in vitro transformation all cell lines (except v-src) were negative for the expression of [H2O2CA + PGE(S)] phenotype and remained equally low-tumorigenic; (2) independently of the types of genes initially transforming the cells, in vivo tumor progression was consistently leading to the replacement of parental cells by cells expressing the [H2O2CA + PGE(S)] phenotype, to 30-200 times increased tumorigenicity and less frequently to metastasizing; (3) the time necessary for selection of cells expressing this phenotype was the same (about 180 days in vivo) for all transformants, except bcl-2; the latter reaching similar values after a significant delay. Thus, common secondary src-like phenotypic cell changes, regardless of initially cell transforming genes are necessarily selected during tumor progression in vivo.