CELL TRANSFORMING GENES AND TUMOR PROGRESSION - IN-VIVO UNIFIED SECONDARY PHENOTYPIC CELL CHANGES

We have earlier shown that Syrian hamster cells spontaneously transfor med 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 (antioxid ant) activity and the ability to release PGE(2) upon contact with NK c ells. In contrast, RSV-SR-(v-src)-transformed cells acquire the [H2O2C A + PGE(S)] phenotype and high tumorigenicity during in vitro transfor mation, i.e., without preliminary in vivo selection. In the present st udy, the possible influence of different transforming genes on the rat es 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)] pheno type, the extent of tumorigenic and spontaneous metastasizing activiti es were examined before and during in vivo cells selection in s.c. gro wing tumors. Our results demonstrate that: (1) after in vitro transfor mation 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 cell s, in vivo tumor progression was consistently leading to the replaceme nt of parental cells by cells expressing the [H2O2CA + PGE(S)] phenoty pe to 30-200 times increased tumorigenicity and less frequently to met astasizing; (3) the time necessary for selection of cells expressing t his phenotype was the same (about 180 days in vivo) for all transforma nts, except bcl-2; the latter reaching similar values after a signific ant delay. Thus, common secondary src-like phenotypic cell changes, re gardless of initially cell transforming genes are necessarily selected during tumor progression in vivo. (C) 1998 Wiley-Liss, Inc.