We examined factors promoting malignant progression using a weakly malignant variant cell line, ER-1, derived from c-SST-2, a rat mammary carcinoma. ER-1 cells were converted to a highly malignant phenotype (highly tumorigenic, metastatic, invasive in vitro) by the in vitro/in vivo interaction with host cells reactive to foreign body. Epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) produced by host reactive cells, transiently enhanced the tumorigenicity and in vitro invasiveness of ER-1 cells into an endothelial cell monolayer. The host reactive cells also produced oxygen radicals and induced mutations in ER-1 cells. It is speculated that mutations induced by host reactive cells cause cellular diversification, including the emergence of highly malignant variant cells whose growth is selectively promoted by growth factors such as EGF and TGF-beta.