Astrocytes contribute to the brain-metastatic specificity of melanoma cells by producing heparanase

Neurotrophins (NTs) modulate the brain invasion of melanoma cells and the activity of an extracellular matrix degradative enzyme, heparanase, that has been recently cloned. Heparanase degrades the heparan sulfate proteoglycans (HSPGs) and is a critical mediator of tumor metastasis and angiogenesis. Because astrocytes are among the first brain cells encountered by extravasating melanoma cells, they may play important roles in the development of brain metastases. To test this hypothesis, we used purified in vitro astrocyte cultures and found that they express heparanase transcript and functional enzyme that were up-regulated by the prototypic NT, nerve growth factor. Coincubation of astrocytes (or their conditioned medium) with brain-metastatic cells resulted in a superadditive effect on heparanase activity and up to an 8-fold increase of in vitro chemoinvasion using purified HSPGs. These observations indicate that astrocytes significantly contribute to the brain colonization of melanoma cells via heparanase-driven modalities.