NERVE GROWTH-FACTOR EFFECTS ON HUMAN AND MOUSE MELANOMA CELL INVASIONAND HEPARANASE PRODUCTION

The role of growth factor networks in regulating the progression of hu man melanocytes towards tumorigenicity and ultimately the malignant ph enotype is poorly understood. In particular, the autocrine and paracri ne influences that modulate cellular invasion and extracellular matrix degradative enzymes of melanoma cells remain undefined at the molecul ar level. We report here that nerve growth factor (NGF) can modify som e metastasis-associated cellular properties of human and mouse melanom a cells. Treatment of early-passage human metastatic melanoma cells (M eWo) or their variants (3S5, 70W) with biologically active 2.SS NGF re sulted in (a) delayed density-dependent inhibition of melanoma cell gr owth; (b) increased in vitro invasion through a reconstituted basement membrane; and (c) time- and dose-dependent induction of heparanase, a heparan-sulfate-specific endo-beta-D-glucuronidase associated with hu man melanoma metastasis. These effects of NGF were most marked in the 70W brain-colonizing cells (70W > MeWo > 3S5). The NGF enhancement of heparanase secretion was not species-specific, since it was also obser ved in murine B16 melanoma cells; the highest NGF stimulation of hepar anase was found in brain-colonizing murine B16-B15b variant (B16-B15b > B16-BL6, B16-F10, B16-F1). NGF also increased the invasive capacity of the human 70W and murine B16-B15b sublines in a chemoinvasion assay performed with filters coated with purified heparan sulfate proteogly can (HSPG). The enhancement of chemotactic response and heparanase pro duction was detected at NGF concentrations sufficient to fully saturat e both low- and high-affinity NGF receptors (NGFR), the neurotrophin r eceptor (p75) and the trkA gene product, respectively. The results sug gest that, in addition to the effects of NGF on cellular development a nd differentiation within the peripheral and central nervous systems, NGF can exert changes in the invasive properties of neuroectoderm-deri ved melanoma cells. (C) 1993 Wiley-Liss, Inc.