CONSTITUTIVE MIGRATION AND EXPRESSION OF 3 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 H a-ras transformed rat liver epithelial cells revealed differences of d iagnostic relevance. The normal cells are induced to migrate by EGF/TG F alpha and to express a set of secreted proteins including fibronecti n, EIP-1/PAI-1, and MEP cathepsin L, which the malignant, constitutive ly migratory cells express constitutively. Only the transformed cells produce proteins of Mr 58/60,000 identified by peptide sequencing as s tromelysin-1. The constitutively migratory cells produce invasive tumo rs and, after intravenous injection, metastatic colonies in the lung ( 'experimental metastasis'). The results demonstrate specific differenc es between the migration/invasion of normal and malignant epithelial c ells, with PAI-1 as a general biochemical marker for migration/invasio n. Constitutive migration and the described gene expression pattern ar e proposed as in vitro indicators of an invasive phenotype. EGF induci bility of the transformed cells to maximal migration and to an increas ed expression of stromelysin indicates susceptibility to a paracrine s timulation of malignancy.