Constitutive migration and expression of three protease systems define in vitro the malignant phenotype of Ha-ras transformed rat liver epithelial cells

: The analysis of migration and gene expression patterns of normal and Ha-ras transformed rat liver epithelial cells revealed differences of diagnostic relevance. The normal cells are induced to migrate by EGF/TGF alpha and to express a set of secreted proteins including fibronectin, EIP-1/PAI-1, and MEP cathepsin L, which the malignant, constitutively migratory cells express constitutively. Only the transformed cells produce proteins of Mr 58/60,000 identified by peptide sequencing as stromelysin-1. The constitutively migratory cells produce invasive tumors and, after intravenous injection, metastatic colonies in the lung ('experimental metastasis'). The results demonstrate specific differences between the migration/invasion of normal and malignant epithelial cells, with PAI-1 as a general biochemical marker for migration/invasion. Constitutive migration and the described gene expression pattern are proposed as in vitro indicators of an invasive phenotype. EGF inducibility of the transformed cells to maximal migration and to an increased expression of stromelysin indicates susceptibility to a paracrine stimulation of malignancy.