MALIGNANT-MELANOMA METASTASIS TO BRAIN - ROLE OF DEGRADATIVE ENZYMES AND RESPONSES TO PARACRINE GROWTH-FACTORS

Mouse and human melanoma cells metastatic to the brain express degrada tive enzyme activities that are used for invasion of brain basement me mbrane and parenchyma. Compared to poorly metastatic or lung- or ovary -metastatic murine melanoma lines, the brain-metastatic sublines secre ted higher levels of a variety of degradative enzymes. Brain-metastati c murine and human melanoma cells also degraded subendothelial basemen t membrane. and reconstituted basement membrane at rates higher than o ther metastatic melanoma cells. Ln some cases these degradative activi ties in mouse and human melanoma cells can be induced by paracrine fac tors known to be present in the brain parenchyma, such as nerve growth factor (NGF). NGF stimulates the expression of degradative enzymes, s uch as the endo-beta-glucuronidase heparanase, that are important in b asement membrane penetration but this factor does not stimulate melano ma cell growth. The growth of brain-metastasizing melanoma cells appea rs to be stimulated by other paracrine growth factors, such as paracri ne transferrin. Melanoma cells metastatic to brain express higher numb ers of transferrin receptors and respond and proliferate at lower conc entrations of transferrin than do melanoma cells metastatic to other s ites or poorly metastatic melanoma cells. The results suggest that deg radation and invasion of brain basement membrane and responses to para crine neurotrophins and paracrine transferrins are important propertie s in brain metastasis of murine and human malignant melanoma cells.