Correlation of overexpression of the low-affinity p75 neurotrophin receptor with augmented invasion and heparanase production in human malignant melanoma cells

The role of growth factor receptors in regulating the progression of human melanocytes toward tumorigenicity and ultimately a malignant phenotype is p oorly understood. In particular, the autocrine and paracrine influences tha t modulate cellular invasion and extracellular matrix (ECM)degradative enzy mes in melanoma cells remain undefined at the molecular level, The low-affi nity p75 neurotrophin receptor (p75(NTR)), a cysteine-rich transmembrane gl ycoprotein, is frequently expressed in advanced stages of human melanoma, b ut the biological consequences of this expression are unknown. p75NTR,,, en hance the invasive potential of brain-metastatic melanoma cells in vitro. W e have extended here these results and related the level of p75(NTR) in hum an metastatic melanoma cells to their invasive potential to target organs o ther than brain, Fluorescence activated cell sorting (FACS) analysis showed that 3 melanoma cell lines (SK-MEL-146, SK-MEL-119, 70W) had differential p75NTR contents, whereas SK-MEL-147 cells had elevated amounts of p75NTR. T WO Other melanoma cell lines (SK-MEL-94, SK-MEL-110) with point mutations i n the p75NTR transmembrane domain had reduced (SK-MEL-94) or absent (SK-MEL -110) p75NTR, We also examined these cell lines for presence of TrkA recept or, the high affinity receptor for nerve growth factor (NGF), the prototypi c neurotrophin. No TrkA receptor expression was detected in any of the cell lines. The extent of p75NTR expression correlated with the capability of N GF to promote cellular invasion and with production of heparanase, an impor tant ECM-degradative enzyme. Melanoma cells sorted for high p75NTR expressi on (p75(NTR-H) cells) had markedly greater (9- to 13-fold increase) invasiv e capabilities in response to NGF exposure than those sorted for low p75NTR expression (p75(NTR-L) cells). Additionally, NGF induced a 8- to 10-fold i ncrease of heparanase activity in p75(NTR-H) cells, Thus, we propose that p 75(NTR)-mediated trophic support profoundly affects melanoma cell invasion to neurotrophin rich organs. (C) 1999 Wiley-Liss, Inc.