EXPERIMENTAL METASTASIS AND DIFFERENTIATION OF MURINE MELANOMA-CELLS - ACTIONS AND INTERACTIONS OF FACTORS AFFECTING DIFFERENT INTRACELLULAR SIGNALING PATHWAYS

Various factors that modulate the differentiation of malignant cells a re known to affect their experimental metastatic potential (EMP), or l ung colonization after intravenous injection into syngeneic animals. H owever, some results and conclusions on the relation between cell diff erentiation and metastasis have appeared to conflict. We have reanalys ed this by measurement of EMP of B16 melanoma sublines after culture w ith agents or conditions that acted on differentiation through various intracellular pathways. All tested agents did affect the EMP. EMP was usually positively correlated with differentiation under diverse cond itions, but exceptions showed that there is no direct causal connectio n. Nor could all findings be explained in terms of cell proliferation or expression of major histocompatibility antigens. Some data helped t o explain disparities between previous reports. Specific novel finding s included the following. The stimulation of EMP by melanocyte-stimula ting hormone (MSH) as well as all other tested effects of MSH were pre vented by extended exposure to 12-O-tetradecanoyl phorbol acetate (TPA ), suggesting a requirement for protein kinase C activity as well as G -protein coupling in MSH action. Cells grown with cholera toxin mere a lways more differentiated than untreated cells, but the EMP could be e ither markedly increased or markedly decreased by cholera toxin under different conditions. The basic culture medium apparently determined t his striking reversal. The EMP was also significantly affected by the extracellular pH.