Malignant transformation of NIH 3T3 fibroblasts by human c-sis is dependent upon the level of oncogene expression

High‐level expression of the c‐sis oncogene, which encodes the β chain of platelet‐derived growth factor, transforms immortalized rodent fibroblasts in vitro to a malignant phenotype. c‐sis gene expression has been demonstrated in a variety of human tumors, although generally at levels much lower than those shown to transform cells in vitro. We examined the effect of lower levels of c‐sis expression on the phenotype of NIH 3T3 fibroblasts. Clones with various levels of c‐sis expression were generated by transfecting NIH 3T3 cells with a plasmid that expressed the human c‐sis cDNA and the TN5 neomycin‐resistance gene. G418‐resistant clones, which expressed the c‐sis cDNA, were selected and characterized. Alterations in the phenotype of the clones that expressed c‐sis ranged from increased growth in soft agar to malignant tumor formation in nude and syngeneic mice. Increased levels of c‐sis cDNA expression correlated with the acquisition of features of transformation in a dose‐dependent manner and altered the cellular phenotype in a manner consistent with the progression of cells towards malignancy. These data support a model in which low levels of sis gene expression in tumors contribute to the acquisition of some features of transformation but require complementation by other genes or factors to produce a fully malignant phenotype. © 1992 Wiley‐Liss, Inc.