5-BROMO-2-DEOXYURIDINE REGULATES INVASIVENESS AND EXPRESSION OF INTEGRINS AND MATRIX-DEGRADING PROTEINASES IN A DIFFERENTIATED HAMSTER MELANOMA CELL

Cell interactions with the extracellular matrix play a critical role i n regulating complex processes such as terminal differentiation and tu mor progression. In these studies we describe a melanoma cell system t hat should be useful in addressing the regulation of cell-matrix inter actions and the roles they play in regulating differentiation and cell invasiveness. CS (suspension)-1 melanoma cells are relatively well di fferentiated: they are melanotic, responsive to melanocyte-stimulating hormone, and express TA99, a melanosome membrane differentiation mark er. Their repertoire of integrin receptors for extracellular matrix li gands is limited; in particular, they lack receptors for vitronectin, accounting for the observation that they are nonadherent when cultured in the presence of serum. CS-1 cells are non-invasive as well, and ex press low levels of both metalloproteinases and activated plasminogen activators. Treatment of these cells with melanocyte-stimulating hormo ne causes them to increase melanin production and assume an arborized phenotype, suggesting that it promotes their further differentiation. In contrast, treatment of CS-1 with the thymidine analog 5-bromo-deoxy uridine, converts them to a highly invasive cell population (termed BC S-1) that loses its differentiated properties and responsiveness to me lanocyte-stimulating hormone, acquires a broad integrin repertoire (in cluding vitronectin receptors), and expresses elevated levels of metal loproteinases and activated urokinase. From these observations and fin dings of others on BrdU treatment of other developmental lineages, we hypothesize that BrdU both suppresses differentiation and promotes inv asiveness of CS-1 cells. The demonstrated manipulability of CS-1 cells should make them extremely useful for studying the regulation of both terminal differentiation and tumor progression in the melanocyte line age.